Syntheses and conformational analyses of new naphth[1,2-e][1,3]oxazino[3,2- c]quinazolin-13-ones

Article abstract of DOI:10.1016/j.tet.2012.04.026

The syntheses of naphth[1,2-e][1,3]oxazino[3,2-c]quinazolin-13-one derivatives (3a-f) were achieved by the solvent-free heating of benzyloxycarbonyl-protected intermediates (2a-f) with MeONa. For intermediates 2a-f, prepared by the reactions of substituted aminonaphthols with benzyl N-(2-formylphenyl)carbamate, not only the expected trans ring form B and chain form A¹, but also the rearranged chain form A² as a new tautomer were detected in DMSO at room temperature. The quantity of A ² in the tautomeric mixture was changed with time. Conformational analyses of the target heterocycles 3a-f by NMR spectroscopy and accompanying theoretical calculations at the DFT level of theory revealed that the oxazine ring preferred a twisted chair conformation and the quinazolone ring was planar. Besides the conformations, both the configurations at C-7a and C-15 and the preferred rotamers of the 1-naphthyl substituent at C-15 were assigned, which allowed evaluation of the aryl substituent-dependent steric hindrance in this part of the molecules. Configurational assignments were corroborated by quantifying the ring current effect of 15-aryl in terms of spatial NICS.

Full text of DOI:10.1016/j.tet.2012.04.026

Tetrahedron 68 (2012) 4600e4608
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Syntheses and conformational analyses of new naphth[1,2-e][1,3]oxazino[3,2-c]
quinazolin-13-ones
a
a
b
b
b,
*
ꢀ
€ € €
ꢀ
ꢀ
Renata Csutortoki , Istvan Szatmari , Andreas Koch , Matthias Heydenreich , Erich Kleinpeter
,
a
,
*
€ €
Ferenc Fulop
a
€
€
Institute of Pharmaceutical Chemistry and Stereochemistry Research Group of 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:
The syntheses of naphth[1,2-e][1,3]oxazino[3,2-c]quinazolin-13-one derivatives (3aef) were achieved by
the solvent-free heating of benzyloxycarbonyl-protected intermediates (2aef) with MeONa. For in-
termediates 2aef, prepared by the reactions of substituted aminonaphthols with benzyl N-(2-
formylphenyl)carbamate, not only the expected trans ring form B and chain form A1, but also the re-
arranged chain form A2 as a new tautomer were detected in DMSO at room temperature. The quantity of
A2 in the tautomeric mixture was changed with time.
Conformational analyses of the target heterocycles 3aef by NMR spectroscopy and accompanying the-
oretical calculations at the DFT level of theory revealed that the oxazine ring preferred a twisted chair
conformation and the quinazolone ring was planar. Besides the conformations, both the configurations at
C-7a and C-15 and the preferred rotamers of the 1-naphthyl substituent at C-15 were assigned, which
allowed evaluation of the aryl substituent-dependent steric hindrance in this part of the molecules.
Configurational assignments were corroborated by quantifying the ring current effect of 15-aryl in terms
of spatial NICS.
Received 28 February 2012
Received in revised form 5 April 2012
Accepted 6 April 2012
Available online 14 April 2012
Keywords:
Naphthoxazinoquinazolinones
Aminonaphthols
NMR spectroscopy
Conformational analysis
Theoretical calculations
Ring current effect
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
or by starting the synthesis from salicylaldehyde, leading to 1-
(amino(2-hydroxyphenyl)methyl)-2-naphthol, followed by ring
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 This
reaction basically involves the addition of a carbon nucleophile to
an iminium ion, resulting in a secondary or tertiary amine de-
rivative, depending on the nature of the substrate used. 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
Naphth[1,2-e][1,3]oxazino[3,4-c][1,3]benzoxazine and naphth[1,2-
e][1,3]oxazino[3,2-c][1,3] benzoxazine derivatives have been
prepared by the insertion of an additional hydroxy group
through the reactions of aminonaphthols with salicylaldehyde,4
closure with oxo compounds.5 The syntheses of 8-substituted
10,11-dihydro-8H,15bH-naphth[1,2-e][1,3]oxazino[4,3-a]isoquino-
lines have been achieved through the cyclization of 1-(b-hydrox-
ynaphthyl)-1,2,3,4-tetrahydroisoquinoline with formaldehyde,
phosgene, p-nitrobenzaldehyde or p-chlorophenyl isothiocyanate,6
and the syntheses of naphth[1,2ee][1,3]oxazino[2,3-a]isoquino-
lines via unexpected reactions between 1-aminobenzyl-2-naphthol
analogues and 6,7-dimethoxy-3,4-dihydroisoquinoline were-
recently described.7
We earlier reported the syntheses and conformational analyses
of naphth[1,2ee][1,3]oxazino[3,4-c]quinazoline derivatives from 1-
(amino(2-aminophenyl)methyl)-2-naphthol, which was prepared
by the reactions of 2-naphthol, 2-nitrobenzaldehyde and tert-butyl
carbamate or benzyl carbamate.8 In order to investigate the in-
fluence of the anellation on the conformation of naphth[1,2-e][1,3]
oxazinoquinazolines, our present aims were to synthesize new
naphth[1,2-e][1,3]oxazino[3,2-c]quinazoline derivatives, and to
achieve the conformational analyses of these new polycyclic com-
pounds by NMR spectroscopy and accompanying molecular
modelling.
* Corresponding authors. Tel.: þ49 331 977 5210/5211; fax: þ49 331 977 5064;
Quinazolinone derivatives have attracted considerable atten-
tion in view of the broad range of their pharmacological
e-mail addresses: ekleinp@uni-potsdam.de (E. Kleinpeter), fulop@pharm.u-sze-
€ €
ged.hu (F. Fulop).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.026

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activities, e.g., analgesic, anti-inflammatory, antibacterial, anti-
cancer, sedative, vasodilator, anticonvulsant and antihypertensive
activities.9
benzyloxycarbonyl-protected intermediates (2a and 2c, Scheme 1).
The mixtures were stirred for 2e4 days at room temperature,
during which white crystals separated out. The crystalline products
(2a and 2c) were filtered off and washed with cold EtOH.
2. Results and discussion
2.1. Syntheses
Our efforts to remove the protecting group either by catalytic
(Pd/C) hydrogenation at atmospheric pressure or with 33% HBr/
AcOH at room temperature led to the decomposition of 2a and 2c
instead of formation of the desired amino derivatives. In additional
experiments, the benzyloxycarbonyl-protected intermediates (2a
and 2c) were heated with MeONa (30 mol %) under solvent-free
For the synthesis of the proposed naphthoxazinoquinazolines,
the preparations of 2-(2,3-dihydro-1H-naphth[1,2-e][1,3]oxa-
3'
H
CbzHN 2'
11
N 11a
13
4'
5'
O
H
CHO
10
9
R
NH2 HCl
OH
1'
H
R
N
R
N
7b
6'
NHCbz
15
MeONa
∇
7a
8
5
1
8
8a
1
OH
15a
15b
7
6
Et3N, EtOH, r.t.
O
2
2
6a
3
15a
4a
4a
3
6
4
1a-f
4
5
2a-fA1
3a-f
CbzHN
CbzHN
N
CbzHN
H
H
H
H
H
H
R
N
R
R
N
O
OH
O
2
2a-fB
2a-fA
2a-fC
a
b
c
d
e
f
R = H: ; p-Cl-Ph: ; Ph: ; p-OMe-Ph: ; 1-Nph: ; 2-Nph:
Scheme 1. Syntheses of naphthoxazinoquinazolin-13-ones (3aef).
zin-3-yl)aniline and 2-(1-phenyl-2,3-dihydro-1H-naphth [1,2-e]
[1,3]oxazin-3-yl)aniline as starting materials were planned. In our
initial experiments, we attempted to prepare the target compounds
through the condensations of 1-aminomethyl-2-naphthol or 1-
aminobenzyl-2-naphthol with 1.1 equiv of 2-aminobenzaldehyde.
However, because of the low reactivity of 2-aminobenzaldehyde
(which can be explained by the presence of its imino mesomer
structure10), there was no conversion. An attempt was made to shift
the equilibrium towards the aldehyde function by using 1.5 equiv of
Et3N or HCl/EtOH, but even on the use of different reaction condi-
tions (in EtOH at room temperature, or the application of micro-
wave irradiation in EtOH at 60e90 ꢀC), the target compounds could
not be isolated, e.g., at room temperature there was no conversion,
while the higher temperatures led to decomposition of the starting
aminonaphthol.
In further experiments, the condensations of 1-aminomethyl-
2-naphthol or 1-aminobenzyl-2-naphthol with 1.1 equiv of 2-
nitrobenzaldehyde were attempted in MeOH in order to synthe-
size 2-(2,3-dihydro-1H-naphth[1,2-e][1,3]oxazin-3-yl)aniline and
2-(1-phenyl-2,3-dihydro-1H-naphth[1,2-e][1,3]oxazin-3-yl)ani-
line. These reactions did lead to the formation of the expected nitro
derivatives. However, although the transformation of the nitro
function to an amino group should have been achieved for the
syntheses of 2-aminophenyl-substituted naphthoxazines, neither
catalytic (Pd/C) hydrogenation nor reduction with Fe powder in the
presence of concentrated HCl resulted in isolation of the desired
amino derivatives, and after even a short reaction time de-
composition of the starting naphthoxazines was observed on TLC.
As a new synthetic strategy, aminonaphthols were reacted with
benzyl N-(2-formylphenyl)carbamate to afford the corresponding
conditions at their melting temperatures. After reaction times of
10 and 30 min, when TLC showed no presence of the starting ma-
terials, the reaction mixtures were cooled down and the products
(3a and 3c) were isolated by treatment with EtOH. This synthetic
pathway was extended for the preparation of naphthox-
azinoquinazolinones containing different aryl substituents at po-
sition 15 (p-ClePh:3b, p-OMeePh: 3d, 1-naphthyl: 3e, and 2-
naphthyl: 3f) (Scheme 1). It should be mentioned that in the
cases of 3d and 3f a doubled amount of MeONa (60 mol %) in-
creased the yields (from 31% to 60% for 3d, and from 37% to 51% for
3f; Table 5). For 3f, a different work-up procedure was applied; the
solid residue was extracted with EtOAc and dried (Na2SO4), and
after evaporation of the solvent the residue was crystallized from
a mixture of n-hexane:EtOAc.
In CDCl3 at 300 K, 2aef can participate in three-component
tautomeric mixtures containing diastereomeric ring forms (B and
C) besides the chain form (A).11 Because of the low solubility of
intermediates 2aef in CDCl3, the NMR spectra were recorded in
DMSO. The total assignment of 2c revealed the presence of a new
tautomeric chain form (A2) besides the trans ring form B and chain
form A1. Through the use of 2D NMR techniques, the structure of A2
was identified as a tautomeric form of A1, in which the imine double
bond is in an
a position relative to the naphthyl ring, as depicted in
Scheme 1. To establish whether this unexpected rearrangement is
influenced by the nature of substituent R, the NMR spectra of 2a,b
and 2def (Table 1, entries 1, 4, 14, 19 and 24) were recorded on
solutions of 15 mg of crystals in 700 mL of deuterated DMSO. The
ratio of A1 to A2 did differ, but our attention then focused on the
influence of time. Thus, the spectra of 2bef were recorded after the
solutions had been allowed to stand for 4 h or 3, 4 or 7 days. In the

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Table 1
Table 1 shows that the standing time has a characteristic in-
Tautomeric ratios for 2aef in DMSO at 300 K
fluence on the tautomeric ratios. In all cases (2bed,f), the amount
of A2 increases, while those of B and A1 decrease as time passes. It
can also be concluded from Table 1 that the formation of A2 (after
standing for 7 days) is the highest for the electron-donating sub-
stituent p-OMe. To prove the reversibility of the process in DMSO
(the presence of a tautomeric equilibrium), 40 mg of 2c was dis-
solved in DMSO (2 mL, corresponding to the concentration used for
the NMR measurements) and the solution was left to stand at room
temperature for 7 days. A sample from this mixture was then
evaporated to dryness, and dissolved again in deuterated DMSO,
after which its NMR spectrum was run. The tautomeric composition
observed was similar to that after the dissolution of crystalline 2c.
Even if 2aefC could not be isolated the minimum-energy
structure of this compound and of the corresponding isomers
2aefB were computed and the results for 2bB and 2bC, re-
spectively, are given in Fig. 1a. Trans-isomers (2aefB) were found to
be between 1.28 kcal/mol and 3.43 kcal/mol more stable in agree-
ment with the experiment. The trans position of the protons H-7a
and H-15 is readily visible (cf. Fig. 1a); the corresponding NOE
cannot be developed as aforementioned (vide supra).
During the ring closure reaction of 2bef with MeONa, the for-
mation of two diastereomers is possible; the diastereomeric ratio
was therefore checked by NMR spectroscopy on the crude products.
It was found that only one diastereomer was present in all five
cases. The preliminary NOE check on purified 3bef adequately
proved the trans arrangement of H-15 and H-7a (Scheme 1). The
formation of only one diastereomer (trans) in case of naphthox-
azinoquinazolinones 3bef can be explained by the aid of the steric
hindrance of bulky aryl substituents at position 15.
Entries
R
Timea
A
1 (%)
100
82.2
A2 (%)
B (%)
1
2
3
4
5
6
7
8
H 2a
0
d
d
7 days
12 days
0
d
17.8
23.1
8.3
7.8
5.4
2.4
1.3
6.9
5.9
4.0
2.6
2.2
10.6
9.3
1.3
1.0
d
76.9
91.7
81.1
40.5
30.4
18.6
82.6
65.3
38.3
34.2
27.6
89.4
76.7
12.4
5.9
d
p-ClePh 2b
Ph 2c
d
4 h
11.1
54.1
67.2
80.1
10.5
28.8
57.7
63.2
70.2
d
3 days
4 days
7 days
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4 h
3 days
4 days
7 days
0
p-OMeePh 2d
1-Nph 2e
2-Nph 2f
4 h
14.0
86.3
93.1
97.2
d
3 days
4 days
7 days
0
2.8
66.7
67.4
66.4
67.4
67.0
90.9
53.9
19.4
16.3
14.8
33.3
32.6
33.6
32.6
33.0
8.6
7.2
4.4
d
4 h
d
3 days
4 days
7 days
0
d
d
d
0.5
4 h
38.9
76.2
83.7
85.2
3 days
4 days
7 days
d
a
The duration of standing after dissolution of the samples.
case of 2a, form A2 could not be detected even after 12 days (Table 1,
entries 1e3). The reason for this is that, in the lack of an aromatic ring
system, there is no possibility of conjugation with the C]N double
bond in A2. Further proof of the presence of conjugation in form A2 is
that, in the case of 2e, containing a 1-naphthyl ring, the rearranged
formA2, could not bedetected evenafter 7 days. Thiscanbeexplained
by the hindered rotation of the naphthyl ring, which restricts
conjugation of the aromatic system with the C]N double bond.
2.2. Conformational analysis
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 Density functional theory calculations were
Fig. 1. a. Minimum-energy structure of 2bB and 2bC(NHMe instead of NHCOOCH2Ph); b. Global minimum-energy structure of 3a.

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performed at the B3LYP/6-31G** level of theory.13,14 The molecular
modelling software package SYBYL 7.3 was used to display results
and geometries.15 As the NMR measurements were recorded in
DMSO, the energies of the participating conformers were calcu-
lated with consideration of the effect of the solvent via the di-
electric constant
3 ¼46.7. All configurations of 3aef were studied at
the DFT level of theory with respect to the preferred conformers or
conformational equilibria. In 7aH,12H,15bH-naphth[1,2-e][1,3]oxa-
zino[3,2-c]quinazolin-13-one (3a), only one chiral centre is present.
Fig. 1b shows the global minimum-energy structure of 3a.
In consequence of the presence of the aryl substituents at
position 15, the remaining compounds 3bef contain two chiral
centres. Theoretical calculations were performed for all of the
stereoisomers as regards both the configurations of C-15 and C-
7a and the ring interconversions of the two non-aromatic ring
moieties. To begin with compounds 3bed, the results of the
optimization are given in Table 2. It can be concluded from the
relative energy values that the trans arrangement of H-15 and H-
7a is favourable for 3bed (Table 2). The lack of NOESY interaction
between H-15 and H-7a indirectly proved the trans arrangement,
which is indicated by the theoretical calculations at the DFT
level.
Table 2
Calculated energy differences for 3bed
Optimized
geometry
C-15
C-7a
D
Ea
D
Eb
(kcal/mol)
(kcal/mol)
3b
3c
3d
trans
cis
trans
cis
trans
cis
S*
S*
S*
S*
S*
S*
R*
S*
R*
S*
R*
S*
0
5.27
0
5.56
0
5.79
0
5.10
0
5.32
0
5.57
Fig. 2. Minimum-energy structures of the trans and cis diastereomers of 3bed.
Table 3
Calculated energy differences for 3e and 3f
a
In the gas phase.
b
In DMSO as solvent.
H-15eC-20/
H-15eC-10
Optimized
geometry
C-15
C-7a
D
Ea
D
Eb
(kcal/mol)
(kcal/mol)
3e
3f
antic
syn
anti
sync
anti
syn
trans_I
trans_II
cis_I
S*
S*
S*
S*
S*
S*
S*
S*
R*
R*
S*
S*
R*
R*
S*
S*
0
0
4.88
8.27
9.21
0
0.79
5.66
6.25
4.92
8.09
8.78
0
0.78
5.40
5.98
Fig. 2 depicts the minimum-energy structures of the trans and
cis diastereomers of 3bed.
cis_II
As a result of the restricted rotation of the naphthyl substituents
at position 15 around the C-15eC-10 bond in 3e, and around the C-
15eC-20 bond in 3f, four conformers were obtained after the ge-
ometry optimization, i.e., structures with syn and anti positions of
H-15 and C-20 in 3e and of H-15 and C-10 in 3f (cf. Table 3).
The theoretical results in Table 3 demonstrate that the trans
arrangement of H-15 and H-7a is favourable for both 3e and 3f. This
is the case in both the trans and the cis diastereomers of 3e (anti
position of H-15 and C-20). In the trans_I and cis_II geometries of 3e
N-14 is not planar and its relative configuration is R*, while in both
the trans_II and the cis_I geometries of 3e, N-14 was found to be
planar as in the cases of 3aed and 3f. The sterically hindered ro-
tation of the 1-naphthyl substituent around the C-15eC-10 bond led
to the energy difference between the trans_I and trans_II forms of
3e being relatively high: 4.92 kcal/mol (cf. Table 3). Fig. 3 illustrates
the minimum-energy structures of the trans and cis diastereomers
of 3e.
In the trans diastereomers of 3f, the anti position of H-15 and C-
10 was found to be preferred, in contrast with the syn position in the
cis diastereomers. The energy difference between the trans_I and
trans_II forms of 3f was relatively low: 0.78 kcal/mol (Table 3); as
expected, the rotation of the 2-naphthyl substituent around the C-
15eC-20 bond is less sterically hindered than that of the 1-naphthyl
substituent around the corresponding C-15eC-10 bond. Fig. 4 de-
picts the minimum-energy structures of the trans and the cis di-
astereomers of 3f.
trans_I
trans_II
cis_I
syn
anti
cis_II
a
In the gas phase.
In DMSO as solvent.
In these structures, N-14 was found to be not planar and its relative configu-
b
c
ration was R*.
In order to illustrate the differences in the sterically hindered
rotation of the aryl substituents (phenyl, 1-naphthyl or 2-naphthyl)
around the C-15eC-10 or the C-15eC-20 bond in 3c,e and 3f, the
energy was calculated with respect to the deviations of the torsion
angle (in 5ꢀ steps up to -30ꢀ or þ30ꢀ, respectively) from the cor-
responding values in the minimum-energy structures. The energy
values obtained are plotted versus the torsion angle in 3c,e and 3f
in Fig. 5. It is readily concluded that, for a given torsion angle de-
viation, the 1-naphthyl substituent requires a higher energy than
the 2-naphthyl or phenyl substituents. In turn, 2-naphthyl requires
less energy than 1-naphthyl, while the symmetrical phenyl ring
suffers the lowest steric hindrance.
2.3. Anisotropic effects
In order to demonstrate the stereochemistry of the naphth[1,2-
e][1,3]oxazino[3,2ec]quinazolinone derivatives (obtained by

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Fig. 5. Plots of
DE for 3c,e and 3f versus the torsion angle of the rotation about C-
15eC-10 or C-15eC-20.
Fig. 3. Minimum-energy structures of the trans and cis diastereomers of 3e.
Fig. 4. Minimum-energy structures of the trans and cis diastereomers of 3f.
means of DFT calculations and proved only indirectly through the
lack of NOE (H-7a.H-15) information), the ring current effects of
the 15-aryl substituents on H-1 in 3c,e and 3f were computed. For
this purpose, the spatial NICS approach16 was employed. The
through-space NMR shieldings (TSNMRSs) can be visualized16 as
iso-chemical-shielding surfaces (ICSSs) and employed to quantify
the anisotropic effects of functional groups on proton chemical
shifts (to determine the stereochemistry of nuclei proximal to
the functional group),5,17e27 in order to separate the anisotropic
effects of functional groups from the influence of steric
hindrance on the same proton chemical shifts,28 and to visualize
and quantify planar29,30 or spherical (anti)aromaticity31e33 and
chelatoaromaticity.34
Fig. 6. Ring current effects of the phenyl ring in 3c and the 1-naphthyl ring in 3e on H-1.
various sizes and directions (cf. Fig. 6 for 3c (phenyl) and 3e
(naphthyl ring system), respectively) and finally the corresponding
anisotropic effect of the 15-aryl moiety on H-1 was computed
quantitatively. The corresponding values (as shielding values, neg-
ative for deshielding and positive for the shielding of H-1) are given
in Table 4, together with the H-1 chemical shift in 3a as reference.
The coincidence is very good: the anisotropic effect of the 15-
aryl moiety proves to be w0.5 ppm, in complete agreement with
the experiment, and proves the stereochemistry of the naphth[1,2-
e][1,3]oxazino[3,2-c]quinazolinone derivatives 3c,e and 3f.
From the optimized geometries of 3c,e and 3f, the TSNMRSs of
the aryl moieties on C-15 were calculated, visualized by ICCSs of

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Table 4
analyser (Micromass/Waters, Manchester, UK) in positive ion mode.
The elemental compositions of the ions were determined by ac-
curate mass measurements with standard deviation <5 ppm. Per-
fluorokerosene was used as reference compound and the mass
resolution was 5000.
Starting aminonaphthols were synthetized according to litera-
ture methods: 1aed,11 1e40 and 1f.40 2-Aminobenzaldehyde and
benzyl N-(2-formylphenyl)carbamate were prepared on the basis of
syntheses described in the literature.41,42 It should be mentioned
that benzyl N-(2-formylphenyl)carbamate was earlier reported as
a colourless oil,42 but in our experiment it was isolated as white
crystals (mp: 60e62 ꢀC; lit.43 mp: 64e65 ꢀC).
Experimental differences in the chemical shifts d/ppm of H-1 and the anisotropic
effects of 15-aryl in 3c,e,f s/ppm
Comp.
dexp (H-1)
Ddexp/ppm
scalcd/ppm
3a
3c
3e
3f
7.84
7.39
7.22
7.45
0
d
0.45
0.62
0.39
0.56
0.55
0.49
3. Conclusions
The benzyloxycarbonyl-protected intermediates (2aef) were
synthetized by the reactions of substituted aminonaphthol de-
rivatives (1aef) with benzyl N-(2-formylephenyl)carbamate.
When the NMR spectra of 2aef were recorded in DMSO, the spectra
of 2bed,f revealed the presence of a new tautomeric chain form
(A2) besides the trans ring form B and the chain form A1. The ratio of
A1eA2 was studied and found to depend on the time of standing.
Compounds 2aef were transformed to naphth[1,2-e][1,3]oxazino
[3,2-c]quinazolin-13-one derivatives (3aef) by solvent-free heating
with MeONa. The lack of a cross-peak between H-15 and H-7a in
the NOESY NMR spectra of 3bef indirectly proved their trans ar-
rangement, which was indicated by the DFT geometry optimiza-
tion. Both the configurations and conformations of the naphth[1,2-
e][1,3]oxazino[3,2-c]quinazolin-13-one derivatives 3bef were elu-
cidated by theoretical calculations at the DFT level; the (C-15, C-7a)
trans-isomers (in the cases of 3e,f, trans_I) are preferred. The
steric hindrance of the aryl substituents on C-15 was also
studied and found to decrease in the sequence 1-naphthyl>2-
naphthyl>phenyl. Finally, the anisotropic effect of the 15-aryl ring
current on H-1 was calculated: the excellent agreement of the
computational results and experiment proved the stereochemistry
of the naphth[1,2-e][1,3]oxazino[3,2-c]quinazolin-13-one de-
rivatives 3bef deduced from the theoretical calculations.
4.2. General method for the syntheses of benzyloxycarbonyl-
protected intermediates 2aef
Et3N (3.3 mmol) and benzyl N-(2-formylphenyl)carbamate
(3.3 mmol) were added to a solution of the appropriate amino-
naphthol hydrochloride (3 mmol) in EtOH (15 mL). The mixture was
stirred for 2e4 days at room temperature, during which white crystals
separated out. The crystalline products (2aef) were filtered off and
washed with cold EtOH(2ꢁ5 mL). Afterdissolution of the samples, the
chain form A1 was found tobethemajortautomer;thefullassignment
of the NMR signals is therefore described only for A1, while for the
minor forms A2 and B only the characteristic signals are listed.
4.2.1. Compound 2a. White crystals, yield: 1.00 g (81%), mp:
172e174 ꢀC. HR-EIMS: m/z calcd for C26H22N2O3: 410.1625, found
410.1622.
4.2.2. Compound 2aA1 (major tautomer). 1H NMR (600 MHz,
DMSO)
d
¼5.07 (s, 2H, COOCH2), 5.21 (s, 2H, NphCH2), 7.09 (t, 1H, 50-
H, J¼7.5 Hz), 7.20e7.26 (m, 5H, 3-H, 7-H, 6-H, 200-H, 600-H), 7.33e7.37
(m, 3H, 300-H, 500-H, 400-H), 7.40 (t, 1H, 40-H,J¼7.9 Hz), 7.53 (d, 1H, 60-
H, J¼7.9 Hz), 7.75 (d, 1H, 4-H, J¼9.0 Hz), 7.79 (d, 1H, 5-H, J¼9.0 Hz),
8.07 (d, 1H, 8-H, J¼9.0 Hz), 8.22 (d, 1H, 30-H, J¼8.4 Hz), 8.65 (s, 1H,
N]CH), 9.89 (br s, 1H, OH), 12.36 (s, 1H, NH). 13C NMR (150 MHz,
4. Experimental section
4.1. General
DMSO):
d
¼53.6 (NphCH2), 65.8 (COOCH2), 115.2 (C-1), 117.3 (C-30),
118.2 (C-3), 120.4 (C-10), 121.9 (C-50), 122.6 (C-6), 123.0 (C-8), 126.6
(C-7),127.8 (C-200, C-600), 128.0 (C-400),128.1 (C-4a), 128.2 (C-5), 128.5
(C-300, C-500), 129.1 (C-4), 131.4 (C-40), 133.3 (C-8a), 133.6 (C-60), 136.4
(C-100), 139.4 (C-20), 153.1 (COH), 153.2 (COOCH2), 164.8 (N]CH).
Melting points were determined on a Hinotek X-4 type melting
point apparatus and are uncorrected.
The different conformations and configurations of the studied
compounds were preoptimized with the PM3 Hamiltonian.35 The
B3LYP density functional method was selected for all calculations.
The method was based on Becke’s three-parameter hybrid func-
tionals36 and the correlation functional of Lee et al.37 All optimi-
zations were carried out without any restriction at this B3LYP/6-
31G** level of theory.13,14 The self-consistent reaction field
method (SCRF) and the polarizable continuum model (PCM) using
the integral equation formalism variant (IEF-PCM) were applied to
take solvent effects (DMSO) into account.38 Visualization was car-
ried out with the modelling software SYBYL 7.315 and the program
GaussView 2.0.39
4.2.3. Compound 2aB (minor tautomer, characteristic signals). 1H
NMR
d
¼4.50 (s, 2H, COOCH2), 4.74e5.74 (m, 2H, NphCH2), 6.64 (s,
1H, NHCHO), 10.23 (br s, 1H, OH). 13C NMR
(COOCH2), 82.7 (NHCHO).
d
¼40.6 (NphCH2), 63.0
4.2.4. Compound 2b. White crystals, yield: 1.02 g (65%), mp:
178e179 ꢀC. HR-EIMS: m/z calcd for C32H25ClN2O3: 520.1548, found
520.1551.
4.2.5. Compound 2bA1 (major tautomer). 1H NMR (600 MHz,
The 1H and 13C NMR spectra were recorded in DMSO solutions in
5 mm tubes, at room temperature, on a Bruker Avance III spec-
trometer at 600.13 (1H) and 150.61 (13C) MHz, with the deuterium
signal of the solvent as the lock and TMS as internal standard. All
spectra (1H, 13C, gs-H, H-COSY, gs-HMQC, gs-HMBC and NOESY)
were acquired and processed with the standard BRUKER software.
The low-resolution EI mass spectra were obtained with
a GCeMS TRACE DSQ II mass spectrometer (Thermo Fisher Scien-
tific Dreieich, Germany) with an electron energy of 70 eV and
a source temperature of 180 ꢀC, using a direct insertion probe with
a DEP filament for positive ionization mode. The HRMS EI spectra
were recorded with a GC/MS instrument with a time-of-flight mass
DMSO)
d
¼5.19e5.31 (m, 2H, COOCH2), 6.77 (s,1H, PhCH), 6.83 (t,1H,
H-7, J¼7.6 Hz), 7.03e7.08 (m, 1H, 6-H), 7.10 (t, 1H, 50-H, J¼7.6 Hz),
7.13e7.18 (m, 2H, 300-H, 500-H), 7.20e7.29 (m, 2H, 400-H, H-3),
7.34e7.38 (m, 2H, 3000-H, 5000-H), 7.39e7.43 (m, 2H, 200-H, 600-H), 7.46
(t, 1H, 40-H, J¼7.9 Hz), 7.54e7.59 (m, 3H, 2000-H, 6000-H, 60-H), 7.71 (d,
1H, 5-H,J¼8.2 Hz), 7.76 (d, 1H, 4-H, J¼8.9 Hz), 7.81 (d, 1H, 8-H,
J¼8.6 Hz), 8.28 (d,1H, 30-H, J¼8.4 Hz), 8.71 (s,1H, N]CH),10.25 (br s,
1H, OH), 12.63 (s, 1H, NH). 13C NMR (150 MHz, DMSO):
d¼65.9
(COOCH2), 66.2 (PhCH), 117.4 (C-30), 118.0 (C-3),119.2 (C-1), 120.4 (C-
10), 122.1 (C-50), 122.4 (C-6), 125.2 (C-8), 125.8 (C-7), 127.8 (C-400),
127.9 (C-200, C-600), 128.5 (C-5, C-3000, C-5000), 128.6 (C-300, C-500), 128.9
(C-4a), 129.1 (C-2000, C-6000), 129.8 (C-4), 130.9 (C-8a), 132.0 (C-40),

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134.0 (C-60), 135.0 (CCl), 136.5 (C-100), 139.6 (C-20), 142.3 (C-1000),
153.0 (COH), 153.3 (COOCH2), 166.2 (N]CH).
COOCH2), 9.80 (br s, 1H, OH), 10.00 (br s, 1H, HNCOOCH2). 13C NMR
¼54.9 (C]NCH2), 55.3 (OCH3), 65.9 (COOCH2).
d
4.2.6. Compound 2bA2 (minor tautomer, characteristic signals). 1H
4.2.14. Compound 2dB (minor tautomer, characteristic signals). 1H
NMR
¼4.61e4.68 (m, 1H, CHNHCH), 5.01e5.12 (m, 2H, COOCH2),
NMR
d
¼4.35e4.49 (m, 2H, C]NCH2), 5.08 (s, 2H, COOCH2), 9.44 (br
d
s, 1H, OH), 10.11 (br s, 1H, HNCOOCH2). 13C NMR
65.8 (COOCH2).
d
¼54.5 (C]NCH2),
5.61e5.65 (m, 2H, NphCHNH, HNCHO), 9.13 (br s, 1H,
HNCOOCH2). 13C NMR
(HNCHO).
d
¼52.0 (NphCHNH), 66.0 (COOCH2), 78.5
4.2.7. Compound 2bB (minor tautomer, characteristic signals). 1H
NMR
¼4.70e4.75 (m, 1H, CHNHCH), 5.01e5.12 (m, 2H, COOCH2),
d
4.2.15. Compound 2e. White crystals, yield: 0.92 g (57%), mp:
201e203 ꢀC. HR-EIMS: m/z calcd for C36H28N2O3: 536.2094, found
536.2091.
5.61 (d, 1H, HNCHO, J¼13.2 Hz), 5.67 (s, 1H, NphCHNH), 8.95 (br s,
1H, HNCOOCH2). 13C NMR
(HNCHO).
d¼52.0 (NphCHNH), 66.0 (COOCH2), 78.5
4.2.16. Compound 2eA1 (major tautomer). 1H NMR (600 MHz,
4.2.8. Compound 2c. White crystals, yield: 1.08 g (74%), mp:
150e152 ꢀC. HR-EIMS: m/z calcd for C32H26N2O3: 486.1938, found
486.1941.
DMSO)
d
¼5.15e5.30 (m, 2H, COOCH2), 6.70 (t, 1H, 7-H, J¼7.6 Hz),
6.99 (t, 1H, 6-H, J¼7.4 Hz), 7.11 (t, 1H, 50-H, J¼7.5 Hz), 7.25e7.44 (m,
9H, 400-H, NphCH, 3-H, 7000-H, 300-H, 500-H, 6000-H, 200-H, 600-H),
7.45e7.51 (m, 2H, 40-H, 3000-H), 7.60 (d, 1H, 60-H, J¼7.6 Hz), 7.63 (d,
1H, 5-H, J¼8.0 Hz), 7.71 (d, 1H, 4-H, J¼8.6 Hz), 7.84 (d, 1H, 4000-H,
J¼8.2 Hz), 7.88 (d, 1H, 5000-H, J¼8.6 Hz), 8.07 (d, 1H, 2000-H, J¼7.2 Hz),
8.21 (d, 1H, 8000-H, J¼8.6 Hz), 8.25 (d, 1H, 8-H,J¼8.7 Hz), 8.28 (d, 1H,
30-H, J¼8.4 Hz), 8.88 (s, 1H, N]CH), 10.58 (br s, 1H, OH), 12.74 (s, 1H,
4.2.9. Compound 2cA1 (major tautomer). 1H NMR (600 MHz,
DMSO)
d
¼5.20e5.31 (m, 2H, COOCH2), 6.77e6.82 (m, 2H, PhCH, 7-
H), 7.02e7.11 (m, 2H, 6-H, 50-H), 7.22e7.26 (m, 2H, 3000-H, 5000-H),
7.27e7.43 (m, 8H, 2000-H, 6000-H, 3-H, 300-H, 500-H, 200-H, 600-H, 400-H),
7.46 (t, 1H, 40-H, J¼7.9 Hz), 7.55e7.60 (m, 2H, 60-H, 4000-H), 7.70 (d,
1H, 5-H, J¼8.1 Hz), 7.74 (d, 1H, 4-H, J¼9.0 Hz), 7.91 (d, 1H, 8-H,
J¼8.9 Hz), 8.28 (d, 1H, 30-H, J¼8.4 Hz), 8.74 (s, 1H, N]CH), 10.21 (br
NH). 13C NMR (150 MHz, DMSO):
d
¼66.1 (COOCH2), 66.2 (NphCH),
117.5 (C-30), 118.2 (C-3), 119.7 (C-1), 120.6 (C-10), 122.1 (C-50), 122.3
(C-6),123.6 (C-8000), 124.6 (C-8),124.9 (C-2000), 125.2 (C-3000), 125.5 (C-
s, 1H, OH), 12.65 (s, 1H, NH). 13C NMR (150 MHz, DMSO):
d¼66.1
6
000),125.6 (C-7),125.9 (C-7000),127.5 (C-4000),127.7 (C-400),127.9 (C-200,
(COOCH2), 67.2 (PhCH), 117.5 (C-30), 118.0 (C-3), 119.7 (C-1), 120.5
C-600), 128.3 (C-5), 128.5 (C-300, C-500), 128.7 (C-5000), 128.8 (C-4a),
129.8 (C-4), 130.6 (C-8a000), 131.9 (C-40), 132.4 (C-8a), 133.6 (C-4a000),
134.0 (C-60), 136.5 (C-100), 139.1 (C-1000), 139.6 (C-20), 152.1 (COH),
153.3 (COOCH2), 165.0 (N]CH).
(C-10), 122.1 (C-50), 122.3 (C-6), 125.5 (C-8), 125.7 (C-7), 127.1 (C-2000
,
C-6000), 127.4 (C-4000), 127.8 (C-200, C-600), 128.3 (C-5), 128.4 (C-300, C-
500), 128.5 (C-3000, C-5000), 128.9 (C-4a), 129.6 (C-4), 130.3 (C-400), 131.5
(C-8a), 131.9 (C-40), 134.0 (C-60), 136.7 (C-100), 139.6 (C-20), 143.3 (C-
1
000), 152.9 (COH), 153.3 (COOCH2), 165.9 (N]CH).
4.2.17. Compound 2eB (minor tautomer, characteristic signals). 1H
NMR
d
¼4.54e4.60 (m, 2H, COOCH2), 4.67e4.73 (m, 1H, CHNHCH),
4.2.10. Compound 2cA2 (minor tautomer, characteristic signals). 1H
NMR
¼4.36e4.50 (m, 2H, C]NCH2), 5.11 (s, 2H, COOCH2), 9.60 (br
s, 1H, OH), 10.06 (br s, 1H, HNCOOCH2). 13C NMR
¼54.7 (C]NCH2),
65.8 (COOCH2). 2cB (Minor tautomer, characteristic signals):
¼4.67e4.73 (m,1H, CHNHCH), 4.99e5.10 (m, 2H, COOCH2), 5.62 (d,
5.80 (d, 1H, HNCHO, J¼13.6 Hz), 6.46 (s, 1H, NphCHNH), 8.11
d
(br s, 1H, HNCOOCH2). 13C NMR
78.6 (HNCHO).
d¼49.7 (NphCHNH), 65.3 (COOCH2),
d
d
4.2.18. Compound 2f. White crystals, yield: 0.98 (61%), mp:
163e165 ꢀC. HR-EIMS: m/z calcd for C36H28N2O3: 536.2094, found
536.2097.
1H, HNCHO, J¼13.3 Hz), 5.67 (s, 1H, NphCHNH), 8.97 (br s, 1H,
HNCOOCH2). 13C NMR
(HNCHO).
d¼52.7 (NphCHNH), 65.9 (COOCH2), 78.6
4.2.19. Compound 2fA1 (major tautomer). 1H NMR (600 MHz,
4.2.11. Compound 2d. White crystals, yield: 0.90 g (58%), mp:
152e154 ꢀC. HR-EIMS: m/z calcd for C33H28N2O4: 516.2044, found
516.2049.
DMSO)
d
¼5.17e5.32 (m, 2H, COOCH2), 6.70 (t,1H, 7-H, J¼7.6 Hz), 6.95
(s, 1H, NphCH), 7.01 (t, 1H, 6-H, J¼7.4 Hz), 7.12 (t, 1H, 50-H, J¼7.5 Hz),
7.17 (t, 2H, 300-H, 500-H, J¼7.5 Hz), 7.24 (t,1H, 400-H, J¼7.4 Hz), 7.31e7.36
(m, 4H, 3-H, 3000-H, 200-H, 600-H), 7.42e7.49 (m, 3H, 7000-H, 6000-H, 40-H),
7.62 (d, 1H, 60-H,J¼7.6 Hz), 7.69 (d, 1H, 5-H, J¼8.1 Hz), 7.73e7.78 (m,
3H, 4000-H, 4-H, 8000-H), 7.83 (d,1H, 5000-H, J¼7.8 Hz), 7.89 (d, 1H,1000-H,
J¼8.2 Hz), 7.96 (d,1H, 8-H,J¼8.7 Hz), 8.31 (d,1H, 30-H, J¼8.4 Hz), 8.81
(s, 1H, N]CH), 10.25 (br s, 1H, OH), 12.74 (s, 1H, NH). 13C NMR
4.2.12. Compound 2dA1 (major tautomer). 1H NMR (600 MHz,
DMSO)
d
¼3.69 (s, 3H, OCH3), 5.19e5.32 (m, 2H, COOCH2), 6.73 (s,
1H, PhCH), 6.78 (d, 2H, 3000-H, 5000-H, J¼8.6 Hz) 6.83 (t, 1H, 7-H,
J¼8.0 Hz), 7.05 (t, 1H, 6-H, J¼7.5 Hz), 7.10 (t, 1H, 50-H, J¼7.5 Hz),
7.18 (d, 2H, 2000-H, 6000-H, J¼8.5 Hz), 7.28 (d, 1H, 3-H, J¼8.7 Hz),
7.33e7.37 (m, 3H, 300-H, 500-H, 400-H), 7.38e7.42 (m, 2H, 200-H, 600-H),
7.45 (t, 1H, 40-H,J¼7.9 Hz), 7.57 (d, 1H, 60-H, J¼7.5 Hz), 7.70 (d, 1H,
5-H, J¼8.1 Hz), 7.73 (d, 1H, 4-H, J¼9.0 Hz), 7.93 (d, 1H, 8-H,
J¼8.5 Hz), 8.27 (d, 1H, 30-H, J¼8.5 Hz), 8.72 (s, 1H, N]CH), 10.17 (br
(150 MHz, DMSO):
d
¼66.1 (COOCH2), 67.3 (NphCH),117.4 (C-30),118.1
(C-3), 119.6 (C-1), 120.5 (C-10), 122.1 (C-50), 122.3 (C-6), 123.9 (C-1000),
124.8 (C-3000), 125.3 (C-8), 125.6 (C-7), 125.7 (C-6000), 126.2 (C-7000),
127.4 (C-5000),127.7 (C-200, C-600),127.8 (C-8000),127.9 (C-400, C-4000),128.0
(C-8a000),128.3 (C-5),128.4 (C-300, C-500),128.9 (C-4a),129.7 (C-4),131.7
(C-8a), 131.8 (C-4a000), 131.9 (C-40), 134.1 (C-60), 136.5 (C-100), 139.7 (C-
20), 141.1 (C-2000), 152.9 (COH), 153.4 (COOCH2), 166.1 (N]CH).
s, 1H, OH), 12.64 (s, 1H, NH). 13C NMR (150 MHz, DMSO):
d¼55.1
(OCH3), 66.1 (COOCH2), 66.8 (PhCH), 113.7 (C-3000, C-5000), 117.5 (C-
30), 118.1 (C-3), 119.8 (C-1), 120.5 (C-10), 122.1 (C-50), 122.3 (C-6),
125.5 (C-7), 125.6 (C-8), 127.1 (C-2000, C-6000), 127.8 (C-200, C-600),
128.1 (C-5), 128.3 (C-400), 128.5 (C-300, C-500), 128.9 (C-4a), 129.5 (C-
4), 131.7 (C-8a), 131.8 (C-40), 133.9 (C-60), 135.1 (C-1000), 136.5 (C-100),
139.6 (C-20), 152.8 (COH), 153.3 (COOCH2), 157.7. (COCH3), 165.6
(N]CH).
4.2.20. Compound 2fA2 (minor tautomer, characteristic signals). 1H
NMR
d
¼4.39e4.52 (m, 2H, C]NCH2), 5.11 (s, 2H, COOCH2), 9.60 (br
s, 1H, OH), 10.07 (br s, 1H, HNCOOCH2). 13C NMR
65.8 (COOCH2).
d
¼54.8 (C]NCH2),
4.2.21. Compound 2fB (minor tautomer, characteristic signals). 1H
NMR
¼4.71e4.91 (m, 2H, COOCH2), 4.75e4.80 (m, 1H, CHNHCH),
5.71 (d, 1H, HNCHO, J¼13.2 Hz), 5.81 (s, 1H, NphCHNH), 8.92 (br s,
4.2.13. Compound 2dA2 (minor tautomer, characteristic signals). 1H
d
NMR
d
¼3.74 (s, 3H, OCH3), 4.31e4.47 (m, 2H, C]NCH2), 5.13 (s, 2H,

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1H, HNCOOCH2). 13C NMR
(HNCHO).
d
¼53.0 (NphCHNH), 65.9 (COOCH2), 78.5
J¼8.0 Hz), 7.04 (t, 1H, 9-H, J¼7.6 Hz), 7.15 (d, 1H, 6-H, J¼9.1 Hz), 7.21
(s, 1H, PhCH), 7.30 (d, 2H, 20-H, 60-H, J¼7.5 Hz), 7.32e7.42 (m, 7H, 3-
H, 30-H, 40-H, 50-H, 10-H, 1-H, 2-H), 7.51 (d, 1H, 8-H, J¼7.6 Hz), 7.91
(d, 2H, 4-H, 5-H, J¼8.7 Hz), 10.36 (br s, 1H, NH). 13C NMR (150 MHz,
4.3. General method for the synthesis of
naphthoxazinoquinazolin-13-ones (3aef)
DMSO):
d¼51.5 (PhCH), 78.5 (C-7a), 112.7 (C-15a), 114.1 (C-11), 114.4
(C-7b), 118.7 (C-6), 121.9 (C-9), 122.8 (C-1), 124.0 (C-3), 127.2 (C-2),
128.1 (C-40), 128.6 (C-8), 128.7 (C-5, C-20, C-60), 128.8 (C-30, C-50),
128.9 (C-4a), 129.9 (C-4), 130.9 (C-10), 131.0 (C-15b), 136.6 (C-11a),
140.8 (C-10), 150.8 (NHCON), 151.5 (C-6a). HR-EIMS: m/z calcd for
C25H18N2O2 : 378.1363, found 378.1343.
Benzyloxycarbonyl-protected intermediates (3aef) (0.4 mmol)
were heated with MeONa (30 or 60 mol %) under solvent-free
conditions at their melting temperatures. After a reaction time of
10e40 min, when TLC showed no presence of the starting mate-
rials, the reaction mixture was cooled down and the products
(3aee) were isolated by treatment with EtOH (15 mL). The white
crystals that separated out were filtered off and recrystallized from
iPr2O (10 mL). In the case of compound 3f, the solid residue was
extracted with EtOAc (3 x 10 mL). The combined organic extracts
were dried (Na2SO4) and concentrated under reduced pressure. The
residue was crystallized from iPr2O and recrystallized from n-
hexane:EtOAc (10 mL:1 mL). The reaction conditions applied and
the yields of 3aef are listed in Table 5.
4.3.4. (15S*,7aR*)-15-(4-Methoxyphenyl)-7aH,12H,15bH-naphth[1,2-
e][1,3]oxazino[3,2-c]quinazolin-13-one (3d). White crystals, mp:
275e277 ꢀC 1H NMR (600 MHz, DMSO):
d
¼3.72 (s, 3H, OCH3), 6.31
(s, 1H, 7a-H), 6.92 (d, 2H, 30-H, 50-H, J¼8.3 Hz), 6.97 (d, 1H, 11-H,
J¼8.1 Hz), 7.04 (t, 1H, 9-H, J¼7.5 Hz), 7.12e7.18 (m, 2H, 6-H, PhCH),
7.21 (d, 2H, 20-H, 60-H, J¼7.9 Hz), 7.35e7.44 (m, 4H, 3-H, 10-H, 2-H,
1-H), 7.51 (d, 1H, 8-H, J¼7.6 Hz), 7.87e7.92 (m, 2H, 5-H, 4-H), 10.33
(br s, 1H, NH). 13C NMR (150 MHz, DMSO):
d¼51.1 (PhCH), 55.1
(OCH3), 78.4 (C-7a), 113.0 (C-15a), 114.1 (C-11), 114.2 (C-30, C-50),
114.4 (C-7b), 118.7 (C-6), 121.9 (C-9), 122.9 (C-1), 123.9 (C-3), 127.1
(C-2), 128.6 (C-8), 128.7 (C-4), 128.9 (C-4a), 129.8 (C-5), 129.9 (C-20,
C-60), 130.9 (C-10), 131.0 (C-15b), 132.8 (C-10), 136.6 (C-11a), 150.8
(NCONH), 151.4 (C-6a), 158.9 (COCH3). HR-EIMS: m/z calcd for
C26H20N2O3: 408.1468, found 408.1467.
Table 5
Reaction conditions used for the syntheses of 3aef and the isolated yields
Products
MeONa
(mol %)
Reaction
time (min)
Temperaturea
(ꢀC)
Yieldb (%)
3a
3b
3c
3d
3d
3e
3f
30
30
30
30
60
30
30
60
10
20
30
65
40
15
30
20
174
179
152
154
154
203
165
165
70
61
54
31
60
74
37
51
4.3.5. (15S*,7aR*)-15-(Naphthalen-1-yl)-7aH,12H,15bH-naphth[1,2-
e][1,3]oxazino[3,2-c]quinazolin-13-one (3e). White crystals, mp:
275e277 ꢀC 1H NMR (600 MHz, DMSO):
d
¼6.41 (s, 1H, 7a-H),
6.95e7.02 (m, 2H, 11-H, 9-H), 7.15 (d, 1H, 20-H, J¼7.1 Hz), 7.19 (d,
1H, 6-H, J¼8.9 Hz), 7.22 (d, 1H, 1-H, J¼8.4 Hz), 7.31 (t, 1H, 2-H,
J¼7.6 Hz), 7.33e7.42 (m, 3H, 3-H, 10-H, 30-H), 7.47 (d, 1H, 8-H,
J¼7.6 Hz), 7.62 (t, 1H, 60-H, J¼7.5 Hz), 7.69 (t, 1H, 70-H, J¼7.6 Hz),
7.88 (s, 1H, NphCH), 7.90e7.97 (m, 3H, 5-H, 4-H, 40-H), 8.03 (d, 1H,
50-H, J¼8.1 Hz), 8.67 (d, 1H, 80-H, J¼8.6 Hz), 10.49 (br s, 1H, NH).
3f
a
The reactions were performed at the melting temperatures of 2aef.
Isolated yields.
b
13C NMR (150 MHz, DMSO):
d
¼49.4 (NphCH), 78.4 (C-7a), 112.9
4.3.1. 7aH,12H,15bH-Naphth[1,2-e][1,3]oxazino[3,2-c]quinazolin-13-
one (3a). White crystals, mp: 268e270 ꢀC 1H NMR (600 MHz,
(C-15a), 114.1 (C-11), 114.8 (C-7b), 118.6 (C-6), 122.0 (C-9), 122.3
(C-1), 123.4 (C-80), 124.0 (C-3), 125.2 (C-30), 126.3 (C-60), 127.2 (C-
70), 127.3 (C-2), 128.4 (C-8), 128.8 (C-4), 128.9 (C-5), 129.0 (C-50),
129.1 (C-4a), 129.2 (C-20), 130.0 (C-40), 130.7 (C-8a’), 130.9 (C-10,
C-15b), 133.9 (C-4a’), 135.5 (C-10), 136.6 (C-11a), 151.2 (NCONH),
151.8 (C-6a). HR-EIMS: m/z calcd for C29H20N2O2: 428.1519, found
428.1522.
DMSO):
d
¼4.77 (d, 1H, 15-Heq, J¼16.7 Hz), 5.71 (d, 1H, 15-Hax
,
J¼16.7 Hz), 6.63 (s, 1H, 7a-H), 6.98 (d, 1H, 11-H, J¼8.1 Hz), 7.04 (d,
1H, 6-H, J¼8.8 Hz), 7.09 (t, 1H, 9-H, J¼7.5 Hz), 7.41 (t, 1H, 10-H,
J¼7.8 Hz), 7.44 (t, 1H, 3-H, J¼7.5 Hz), 7.51 (d, 1H, 8-H, J¼7.6 Hz), 7.58
(t, 1H, 2-H, J¼7.6 Hz), 7.77 (d, 1H, 5-H, J¼8.9 Hz), 7.84 (d, 1H, 1-H,
J¼8.4 Hz), 7.88 (d, 1H, 4-H, J¼8.1 Hz), 10.22 (br s, 1H, NH). 13C NMR
(150 MHz, DMSO):
d¼40.7 (CH2), 82.7 (C-7a),113.0 (C-15a),114.1 (C-
11), 114.8 (C-7b), 118.6 (C-6), 121.6 (C-1), 121.8 (C-9), 124.1 (C-3),
127.1 (C-2), 128.3 (C-4a), 128.4 (C-8), 128.5 (C-5), 128.7 (C-4), 130.6
(C-15b),130.8 (C-10),137.0 (C-11a),151.2 (NCONH),151.6 (C-6a). HR-
EIMS: m/z calcd for C19H14N2O2: 302.1050, found 302.1058.
4.3.6. (15S*,7aR*)-15-(Naphthalen-2-yl)-7aH,12H,15bH-naphth[1,2-
e][1,3]oxazino[3,2-c]quinazolin-13-one (3f). Beige crystals, mp:
273e275 ꢀC 1H NMR (600 MHz, DMSO):
d
¼6.40 (s, 1H, 7a-H),
6.96e7.04 (m, 2H, 11-H, 9-H), 7.20 (d, 1H, 6-H, J¼9.0 Hz), 7.34e7.40
(m, 4H, 2-H, NphCH, 3-H, 10-H), 7.42e7.54 (m, 4H, 1-H, 70-H, 8-H,
60-H), 7.58e7.65 (m, 2H, 30-H, 10-H), 7.77 (d, 1H, 80-H, J¼8.1 Hz),
7.88e8.00 (m, 4H, 50-H, 5-H, 4-H, 40-H), 10.40 (br s, 1H, NH). 13C
4.3.2. (15S*,7aR*)-15-(4-Chlorophenyl)-7aH,12H,15bH-naphth[1,2-e]
[1,3]oxazino[3,2-c]quinazolin-13-one (3b). White crystals, mp:
292e294 ꢀC 1H NMR (600 MHz, DMSO):
d¼6.29 (s, 1H, 7a-H), 6.98
NMR (150 MHz, DMSO):
d
¼51.8 (NphCH), 78.5 (C-7a), 112.6 (C-15a),
(d, 1H, 11-H, J¼8.2 Hz), 7.05 (t, 1H, 9-H, J¼7.5 Hz), 7.15 (d, 1H, 6-H,
J¼8.9 Hz), 7.19 (s, 1H, PhCH), 7.30 (d, 2H, 20-H, 60-H, J¼8.0 Hz),
7.37e7.45 (m, 6H, 3-H, 10-H, 1-H, 30-H, 50-H, 2-H), 7.51 (d, 1H, 8-H,
J¼7.7 Hz), 7.92 (d, 2H, 4-H, 5-H, J¼8.9 Hz), 10.39 (br s, 1H, NH). 13C
114.1 (C-11), 114.4 (C-7b), 118.8 (C-6), 121.9 (C-9), 122.8 (C-1), 124.0
(C-3), 126.4 (C-30), 126.5 (C-70), 126.6 (C-60), 127.2 (C-2), 127.6 (C-50),
127.9 (C-10), 128.1 (C-80), 128.6 (C-8), 128.8 (C-5), 128.9 (C-4a, C-40),
130.1 (C-4), 130.9 (C-10), 131.1 (C-15b), 132.5 (C-4a’), 132.6 (C-8a’),
136.6 (C-11a), 138.2 (C-20), 150.9 (NCONH), 151.6 (C-6a). HR-EIMS:
m/z calcd for C29H20N2O2: 428.1519, found 428.1543.
NMR (150 MHz, DMSO):
d
¼50.9 (PhCH), 78.5 (C-7a), 112.2 (C-15a),
114.1 (C-11), 114.4 (C-7b), 118.7 (C-6), 121.9 (C-9), 122.7 (C-1), 124.0
(C-3), 127.3 (C-2), 128.6 (C-8), 128.8 (C-4), 128.9 (C-4a, C-30, C-50),
130.1 (C-5),130.5 (C-20, C-60),130.9 (C-10),131.0 (C-15b),132.8 (CCl),
136.6 (C-11a), 139.6 (C-10), 150.8 (NCONH), 151.6 (C-6a). HR-EIMS:
m/z calcd for C25H17ClN2O2: 412.0973, found 412.0971.
Acknowledgements
The authors thank the Hungarian Research Foundation (OTKA
ꢀ
No. K-75433) and TAMOP-4.2.1/B-09/KONV-2010-0005 and the
4.3.3. (15S*,7aR*)-15-Phenyl-7aH,12H,15bH-naphth[1,2-e][1,3]ox-
Deutsche Akademische Austauschdienst (DAAD), project-ID
50368559, for financial support. I.S. acknowledges the award of
azino[3,2-c]quinazolin-13-one (3c). White crystals, mp: 279e281 ꢀC
1H NMR (600 MHz, DMSO):
d
¼6.31 (s, 1H, 7a-H), 6.97 (d, 1H, 11-H,
ꢀ
a Bolyai Janos Fellowship.

€ €
€
4608
R. Csutortoki et al. / Tetrahedron 68 (2012) 4600e4608
ꢀ
ꢀ
ꢀ
17. Toth, G.; Kovacs, J.; Levai, A.; Koch, A.; Kleinpeter, E. Magn. Reson. Chem. 2001,
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