Novel piperidine-fused benzoxazino- and quinazolinonaphthoxazines - Synthesis and conformational study

Article abstract of DOI:10.1016/j.tet.2012.05.048

The reactions of 1-(amino(2-hydroxyphenyl)methyl)-2-naphthol (3) and 1-(amino(2-aminophenyl)methyl)-2-naphthol (6) with glutardialdehyde resulted in the formation of piperidine-fused benzoxazinonaphthoxazine 4 and quinazolinonaphthoxazine 7, respectively,

Full text of DOI:10.1016/j.tet.2012.05.048

Tetrahedron 68 (2012) 6284e6288
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Novel piperidine-fused benzoxazino- and quinazolinonaphthoxazinesdsynthesis
and conformational study
a
a
b
b
b
ꢀ
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Renata Csutortoki , Istvan Szatmari , Matthias Heydenreich , Andreas Koch , Ines Starke ,
a
,
b,
*
*
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Ferenc Fulop , Erich Kleinpeter
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
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a r t i c l e i n f o
a b s t r a c t
Article history:
The reactions of 1-(amino(2-hydroxyphenyl)methyl)-2-naphthol (3) and 1-(amino(2-aminophenyl)
methyl)-2-naphthol (6) with glutardialdehyde resulted in the formation of piperidine-fused benzox-
azinonaphthoxazine 4 and quinazolinonaphthoxazine 7, respectively, both in diastereopure form.
The full conformational search protocols of 4 and 7 were successfully carried out by NMR spectroscopy
and accompanying molecular modelling; the global minimum-energy conformers of all diastereomers
were computed, and the assignments of the most stable stereoisomers, G1tct for 4 and Gt1ct for 7, were
corroborated by spatial NOE information relating to the H7a-H10a-H15b and H,H coupling patterns of the
protons in the flexible part of the piperidine moiety. Additionally, mass spectrometric fragmentation was
investigated in collision-induced dissociation experiments. The elemental compositions of the ions were
determined by accurate mass measurements.
Received 17 April 2012
Accepted 14 May 2012
Available online 22 May 2012
Keywords:
Quinazolines
Naphthoxazines
DFT structural study
Conformational analysis
NMR spectroscopy
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
The highly functionalized aminonaphthols 3 and 6 were further
successfully transformed to benzoxazine- or quinazoline-fused
The Mannich reaction, between formaldehyde, a secondary
amine and a carbon nucleophile, is one of the most important re-
actions in organic synthesis.1,2 In a modified Mannich reaction,
electron-rich aromatic compounds, such as 1- or 2-naphthol are
applied as carbon nucleophiles,3 e.g., for the successful synthesis of
highly functionalized aminonaphthols, such as 1-(amino(2-
naphthoxazines through their reactions with (mainly) mono-oxo
reactants. In order to capitalize on all three functional groups in
compounds 3 and 6 at the same time, our present aim was to in-
vestigate their reactions with dialdehydes, with a view to obtaining
new hetero- and polycyclic compounds (Scheme 1). The hetero-
cyclic moiety in 4 and 7 is flexible, and we therefore carried out
their detailed conformational analysis by NMR spectroscopy and
accompanying molecular modelling. A parallel MS study allowed
some stereochemical conclusions.
hydroxyphenyl)methyl)-2-naphthol
(3)4
and
1-(amino(2-
aminophenyl)methyl)-2-naphthol (6).5
Aminodiol 3 was earlier transformed to naphth[1,2-e][1,3]oxa-
zino[3,4-c][1,3]benz-oxazine derivatives by its reaction with
formaldehyde and benzaldehyde. The ring-closure reactions pro-
ceeded selectively, or in both positions, e.g., the reaction of 3 with
2 equiv of formaldehyde led to the formation of the parent naphth
[1,2-e][1,3]oxazino[3,4-c][1,3]benzoxazine, while for substitution of
the ring system at positions 8 and 10, 3 was first treated with
1 equiv of benzaldehyde, followed by the reaction with formalde-
hyde or phosgene.4 Additionally, the 8,10-substituted naphth[1,2-e]
[1,3]oxazino[3,4-c]quinazoline derivative was isolated from the
ring-closure reaction of diamine 6 with formaldehyde, benzalde-
hyde and/or phosgene.5
2. Results and discussion
2.1. Syntheses
The starting aminodiol (3) was synthetized by the amino-
alkylation of 2-naphthol (1) with 2 equiv of salicylaldehyde in the
presence of ammonia, followed by acidic hydrolysis of the in-
termediate napthoxazine (2) with TFA.4
In order to transform 3 to the desired piperidine-fused benz-
oxazinonaphthoxazine derivative 4, aminodiol 3 was dissolved in
EtOH and 1.1 equiv of aqueous glutardialdehyde solution was
added. The mixture was stirred for 1 day at room temperature,
during which white crystals separated out. Preliminary 2D NMR
€ €
* Corresponding authors. E-mail addresses: fulop@pharm.u-szeged.hu (F. Fulop),
ekleinp@uni-potsdam.de (E. Kleinpeter).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.048

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R. Csutortoki et al. / Tetrahedron 68 (2012) 6284e6288
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Scheme 1. Syntheses of piperidine-fused naphthoxazine derivatives 4 and 7.
measurements on the precipitating crystals suggested the expected
structure of 4 (Scheme 1).
restrictions. All calculations were carried out by using the Gaussian
09 program package.8 Density functional theory calculations were
carried out at the B3LYP/6-31G** level of theory.9a,b The molecular
modelling software package SYBYL 7.3 was used to display results
and geometries.10 As the NMR measurements were recorded in
CD2Cl2, the energies of the participating conformers were calcu-
lated with consideration of the effect of the solvent too (CH2Cl2).
Compounds 4 and 7 were studied in all the configurations at the
DFT level of theory with respect to the preferred conformers and
conformational equilibria. Theoretical calculations were performed
for all of the stereoisomers of 4 and 7 as regards the R/S stereo-
chemistry of the involved chiral centres C7a, C10a, C15b and N16. The
results of the optimization are given in Table 1 for 4 and in Table 2
for 7.
It can be concluded from the relative energies of the stereoiso-
mers that the trans arrangement of H7a and H15b, the cis arrange-
ment of H10a and H15b and the trans arrangement of H7a and H10a
were preferred for both 4 and 7 (Tables 1 and 2); on the energy
hypersurface, the cis/cis/cis and cis/trans/trans isomers display
energies of 6.1 kcal/mol and 3.8 kcal/mol, respectively. These
computational results were corroborated by the NOE measure-
ments on 4 and 7 (vide supra).
The synthesis of the analogous piperidine-fused quinazolino-
naphthoxazine derivative
7 was planned from 1-(amino(2-
aminophenyl)methyl)-2-naphthol (6), which was prepared
according to the literature procedure.5 The reaction of 1, benzyl
carbamate and 2-nitrobenzaldehyde resulted in the formation of 5.
This was followed by removal of the protecting group and reduction
of the nitro group by catalytic (Pd/C) hydrogenation, yielding 6
(Scheme 1).
A mixture of diamine 6 and 1.1 equiv of aqueous glutar-
dialdehyde solution was dissolved in EtOH and stirred at room
temperature. After 3 h, when TLC indicated no more starting ma-
terial, the reaction mixture was concentrated to dryness and the
product was isolated by column chromatography and crystallized
from n-hexane. The 2D NMR spectra of the isolated compound
proved the structure of 7.
During the ring-closure reactions of 3 and 6 with glutar-
dialdehyde, two new asymmetric centres are introduced, and the
formation of four diastereomers is therefore possible; the dia-
stereomeric ratio was checked from the NMR spectra of the crude
products. It was found that only a single diastereomer was formed
during the reaction. In the NOESY spectra of the purified 4 and 7,
the weak interactions between H7a and H15b and between H7a and
H10a proved their trans arrangement, while the presence of a strong
cross-peak between H10a and H15b demonstrated their cis
arrangement.
Figs. 1 and 2 depict the three lowest-energy geometries for 4
and 7, respectively.
Table 1
In order to extend the series of newly synthetized hexacyclic
ring systems, e.g., to the syntheses of pyrrolidine- and azepane-
fused naphthoxazine derivatives, our attention focused on the re-
actions of aminodiol 3 and diamine 6 with succindialdehyde6 and
adipic dialdehyde.7 However, these reactions did not result in the
desired polycyclic compounds either at room temperature or at
higher temperature (80e90 ꢀC, classical heating or MW), e.g., at
room temperature there was no conversion, while the higher
temperature led to decomposition of the starting 3 and 6.
Calculated energy differences for 4
Geometries
H
7ae
H10ae
H
H10a
7ae
D
E (kcal/mol)
DE (kcal/mol)
(in CH2Cl2)
H15b
H15b
(in the gas phase)
G1tct
G2ccc
G3ccc
G4ctt
G5ttc
G6ttc
G7ctt
G8tct
trans
cis
cis
cis
cis
cis
trans
trans
trans
trans
cis
trans
cis
cis
trans
cis
cis
0
0
6.39
6.44
7.62
11.24
11.34
13.15
18.33
6.10
5.97
7.63
11.38
10.84
12.89
18.08
cis
trans
trans
cis
trans
trans
trans
The numbers correspond to the following relative configurations: 1C15b(S*), N16(R*),
C7a(R*), C10(R*); 2C15b(S*), N16(R*), C7a(S*), C10(R*); 3C15b(S*), N16(S*), C7a(S*), C10(R*);
2.2. Conformational analysis
5
6
4C15b(S*), N16(R*), C7a(S*), C10(S*); C15b(S*), N16(R*), C7a(R*), C10(S*); C15b(S*),
16(S*), C7a(R*), C10(S*); 7C15b(S*), N16(S*), C7a(S*), C10(S*); 8C15b(S*), N16(S*), C7a(R*),
C10(R*).
The conformational search protocol involved PM3 geometry
minimization, followed by geometry optimization without
N

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and G3ctt of 7 as the q (half-chair), no (boat), p (twist-chair)
conformers.
The trans isomer of fused ring perhydrooxazines is usually more
stable than the related cis isomer, as reflected in the mass spectra
by a larger abundance of the molecular ion of the trans isomer.12
The mass spectra of similar O,N-heterocycles were studied pre-
viously in detail by means of high-resolution mass spectrometry
(MS) and metastable ion analysis.12e16
The electron ionization mass spectra of 4 and 7 were in-
vestigated and the compositions of the prominent ions were de-
termined via accurate mass measurements. The most important
fragment ions and the elemental compositions are listed in the
Experimental section. Since it is well known that the appearance
potentials of main fragment ions can depend on the stereochem-
istry of the compounds, low-energy mass spectra (20 eV) of 4 and 7
were first recorded (Table 3).
Table 2
Calculated energy differences for 7
Geometries
H
H15b
7ae
H
H15b
10ae
H
H10a
7ae
D
E (kcal/mol)
DE (kcal/mol)
(in CH2Cl2)
(in the gas phase)
G1tct
G2ccc
G3ctt
G4ttc
G4ccc
G5ctt
G6ttc
G7tct
trans
cis
cis
trans
cis
cis
cis
cis
trans
cis
trans
cis
cis
trans
cis
0
0
4.13
5.61
8.19
8.20
10.22
10.48
17.61
3.77
5.46
7.67
7.99
9.88
10.73
17.32
trans
trans
cis
trans
trans
cis
trans
trans
trans
The numbers correspond to the following relative configurations: 1C15b(S*), N16(R*),
C7a(R*), C10(S*); 2C15b(S*), N16(S*), C7a(S*), C10(S*); 3C15b(S*), N16(R*), C7a(S*), C10(R*);
4C15b(S*), N16(S*), C7a(R*), C10(R*); C15b(S*), N16(R*), C7a(S*), C10(S*); C15b(S*),
N16(S*), C7a(S*), C10(R*); 7C15b(S*), N16(R*), C7a(R*), C10(R*); 8C15b(S*), N16(S*), C7a(R*),
C10(S*).
5
6
In order to acquire a deeper insight into the fragmentations of 4
and 7, we also recorded the mass spectra generated by positive elec-
trospray ionization (ESI). The corresponding ions [MþH]þ and the
fragment ionsresulting from ‘In SourceCID’ experiments were used as
precursor ions and their CID fragmentations were studied. The main
results of the ESI-MS/MS measurements are presented in Table 4.
The EI fragmentations differ from the ESI mass spectra in that
ions [MꢁCHO]þ, [MꢁOH]þ and [MꢁC4H7]þ were not found in the
ESI-MS/MS mass spectra. The molecular ion peak is the base peak
for both compounds. The mass spectra of 4 and 7, which differ only
in the benzoxazine 4 and quinazoline 7 ring moieties, reveal very
similar main fragmentation pathways. As expected and character-
istic for naphthoxazine moieties, the EI mass spectra of 4 and 7 are
dominated by fragmentations such as OH loss and ring-cleavage
reactions. OH loss requires hydrogen migration after ionization
and ring opening. Compounds 4 and 7 undergo fragmentation
mainly involving multiple bond cleavages within the fused ring
systems, ionization occurs on the bridgehead N-atom.17 One of the
most important fragmentation routes proved to be the loss of
C5H8N to yield the ion at m/z 247 for 4 and at m/z 246 for 7. The ion
No really preferred conformation of the three flexible saturated/
partly saturated heterocyclic ring moieties (benzoxazine bo and
quinazoline q, respectively, naphthoxazine no and piperidine p)
was found.
The lowest-energy conformers, G1tct for 4 and Gt1ct for 7, of the
two trans/cis/trans isomers are conformationally identical: bo, q
(half-chair), no (twist) and p (chair). The chair conformation of the
piperidine moiety was proved by proton spectrum iteration11 of the
frozen eC10aHeC10H2eC9H2eC8H2eC7aHe unit delivering the
expected large coupling constants 3J(ax,ax) and 2J(ax,eq) and the
3
much smaller J(ax,eq) and 3J(eq,eq) (cf. Fig. 3).
As the two G1tct minimum-energy conformers of 4 and 7 are the
experimentally available ones, the congruence of the experimental
NMR and the computational study can be concluded. For the same
reasons, experimental information concerning the energetically
next lowest conformers is not available: G2ccc of 4 occurs as the bo
(twist), no (boat), p (twist-boat) conformer, G3ccc of 4 as the bo (half-
chair), no (twist-boat), p (chair) conformer and the two N-analogues
G2ccc of 7 as the q (twist-boat), no (half-chair), p (chair) conformers
Fig. 1. Minimum-energy conformers of 4.
Fig. 2. Minimum-energy conformers of 7.

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ESI-MS/MS measurements showed that C17H11Oþ at m/z 231 loses
CHOꢂ and forms C16H1þ0ꢂ at m/z 202.
The ions at m/z 231 resulting from the losses of 97 (C5H9N2) and
98 (C5H8NO) directly from the molecular ions are more abundant in
the case of 4 (100%) than for 7 (20%, Table 3). Additionally, the ions
C4Hþ7 at m/z 55 and C5H8Nþ at m/z 82 are more abundant for 4,
while the ion at m/z 247 resulting from loss of the piperidine ring is
more abundant for 4 (25%) than for 7 (m/z 246, RA 5%). The type of
heteroatom (O for 4, NH for 7) at position 11 also has an effect on
the loss of C2H3Oꢂ to yield the ion at m/z 286 for 4 and m/z 285 for 7.
Previous NMR investigations on naphth[1,2-e][1,3]oxazino[3,4-
c][1,3]benzoxazine revealed the trans orientation of the C15aeC15b
bond to the lone pair of N9, while the preferred conformation of the
benzoxazine and naphthoxazine rings was found to be a twisted
chair.4 The intensities of the fragment ions at m/z 231 (100%) and
m/z 247 (22%) in the mass spectra of 4 can be compared with those
of the corresponding ions, in the mass spectra of naphth[1,2-e][1,3]
oxazino[3,4-c][1,3]benzoxazine.13 Similar intensities of the typical
fragment ions, together with the NMR results (vide supra), cor-
roborate the conformations of the two heterocyclic ring systems in
4dthe twisted chair and the Gt1ct configuration as obtained from DFT
calculations and depicted in Fig. 2.
5,600
5,400
5,200
5,000
In the low-energy mass spectra, the higher RA of the fragment
ions at m/z 286 in 4 (20%) than in 7 (m/z 285 only 5%) proves that
the elimination of C2H3O from 4 is more favourable because of the
higher ring strain in 4. The higher RAs of the fragment ions m/z:
231, 247 and 286 can be explained by the stronger electronic and
steric effects in 4 with the benzoxazine moiety.
3. Conclusions
2,200
2,100
2,000
1,900
1,800
Piperidine-fused benzoxazinonaphthoxazine 4 was synthetized
through the reaction of 1-(amino(2-hydroxyphenyl)methyl)-2-
naphthol (3) with glutardialdehyde, while piperidine-fused qui-
Fig. 3. PERCH iteration of protons H-7aeH-10a of 4 (top: iterated, bottom: observed
spectrum); results : H-10a (5.66), H-10eq (2.10), H-10ax (1.96), H-9ax (1.99), H-9eq
d
(1.765), H-8eq (2.196), H-8ax (1.77), H-7A (4.91); nJ(H,H): 10a,10eq (2.63), 10a,10ax
(2.54), 10a,9ax (0.51), 10a,9eq (0.77), 10eq,10ax (ꢁ13.81), 10eq,9ax (3.845), 10eq,9eq
(2.61), 10eq,8eq (1.94), H-10eq,H-8ax (ꢁ0.25), H-10ax,H-9ax (13.49), H-10ax,H-9eq
(4.37), H-10ax,H-8eq (ꢁ0.335), H-10ax,H-8ax (ꢁ0.39), H-9ax,H-9eq (ꢁ13.67), H-9ax,H-
8eq (3.63), H-9ax,H-8ax (14.12), H-9ax,H-7a (ꢁ0.405), H-9eq,H-8eq (3.06), H-9eq,H-
8ax (4.24), H-9eq,H-7a (ꢁ0.57), H-8eq,H-8ax (ꢁ12.55), H-8eq,H-7a (4.08), H-8ax,H-7a
(9.92).
nazolinonaphthoxazine
7 was prepared analogously from 1-
(amino(2-aminophenyl)methyl)-2-naphthol (6). The most stable
stereoisomers, G1tct for 4 and Gt1ct for 7, were identified by theoretical
calculations at the DFT level of theory, considering the solvent,
corroborated by spatial NOE information between H7a/H10a/H15b
and 1H NMR spectrum iteration: the H,H coupling patterns of the
protons in the flexible part of the piperidine ring moiety proved the
frozen chair conformation.
Table 3
EI-MS data from low-energy (20 eV) mass spectra and relative abundances (RAs) [m/
z (%)] corresponding to the main electron-induced fragmentations of 4 and 7
4. Experimental section
4.1. General
Ions
Compound 4
Compound 7
[MꢁC2H3O]þ
[MꢁC4H7]þ
[MꢁC5H8N]þ
[MꢁC5H9N2]þ
[MꢁC5H8NO]þ
C5H8Nþ
286(20)
274(6)
247(25)
d
285(5)
273(20)
246(5)
231(20)
d
Melting points were determined on a Hinotek X-4 type melting
point apparatus and are uncorrected.
231(100)
82(17)
55(25)
82(3)
55(8)
The different conformations and configurations of the studied
compounds were preoptimized with the PM3 Hamiltonian.18 The
B3LYPdensityfunctional method wasselectedforall calculations. The
method was based on Becke’s three-parameter hybrid functionals19
and the correlation functional of Lee et al.20 All optimizations were
carried out without any restriction at the B3LYP/6-31G** level of
theory.9a,b The self-consistent reaction field method and the integral
equation formalismvariant of the polarizable continuum model were
applied to take solvent effects (CD2Cl2) into account.21 Visualization
was carried out with the modelling software SYBYL 7.3.10
C4Hþ7
C17H11Oþ at m/z 231 is typical for compounds derived from
(1-aminobenzyl)-2-naphthol derivatives. A possible mechanism
for the multiple bond cleavage, required to form C17H11Oþ,
was described previously for naphthoxazinobenzoxazines.13 The
Table 4
Characteristic fragment ions of
composition of the selected precursor ion from ESI positive spectra
4 and 7 as proved by collision-induced de-
The 1H and 13C NMR spectra were recorded on CD2Cl2 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 of 4 and 7 were obtained by
Compd MS from m/z Ions
4
[MþH]þ 330
287[MꢁC2H3O]þ, 249[MꢁC5H7N]þ, 231[MꢁC5H8NO]
231
202[MꢁCHO]þ
7
[MþH]þ 329
231
312[MꢁOH]þ, 246[MꢁC5H8N]þ, 231[MꢁC5H9N2]þ
202[MꢁCHO]þ

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using a GCeMS TRACE DSQ II mass spectrometer (Thermo Fisher
Scientific Dreieich, Germany), with an electron energy of 70 eV and
a source temperature of 180 ꢀC, using a direct insertion probe with
a direct desorption probe filament in positive ion mode. The HRMS
EI spectra were recorded at 70 eV and 20 eV, using a GC/MS in-
strument with a time-of-flight mass analyser (Micromass, Waters,
Manchester, UK) in positive ion mode. Below 20 eV, the production
of ions was not sufficient. The elemental compositions of the ions
were determined by accurate mass measurements with standard
deviation <5 ppm. Perfluorokerosene was used as reference com-
pound and the mass resolution was 5000.
(td, 1H, J¼7.5, 1.1 Hz, 14-H), 6.51 (dd, 1H, J¼8.0, 1.1 Hz, 12-H), 6.59 (d,
1H, J¼7.7 Hz,15-H), 6.97 (t,1H, J¼7.6 Hz,13-H), 7.04 (d,1H, J¼8.9 Hz,
6-H), 7.36 (ddd, 1H, J¼8.1, 6.9, 1.1 Hz, 3-H), 7.49 (ddd, 1H, J¼8.4, 6.9,
1.4 Hz, 2-H), 7.73 (d, 1H, J¼8.9 Hz, 5-H), 7.80 (d, 1H, J¼8.3 Hz, 1-H),
7.81 (d,1H, J¼8.1 Hz, 4-H).13C NMR (150 MHz, CD2Cl2):
¼16.8 (C-9),
d
30.7 (C-10), 31.6 (C-8), 55.2 (C-15b), 67.3 (C-10a), 81.5 (C-7a), 113.6
(C-12),114.9 (C-15c),117.2 (C-14),118.7 (C-6),119.6 (C-15a),123.0 (C-
1), 123.4 (C-3), 127.0 (C-2), 128.3 (C-13), 128.7 (C-4), 128.8 (C-4a),
129.2 (C-15), 129.3 (C-5), 132.9 (C-15d), 142.1 (C-11a), 150.3 (C-6a).
HR-EI-MS formula and RA (%): [M]þ. (100) m/z calcd for
C22H20N2O: 328.1570, found 328.1579; [MꢁOH]þ (70) m/z calcd for
C22H19N2: 311.1543, found 311.1539; [MꢁCHO]þ (8) m/z calcd for
C21H19N2: 299.1543, found 299.1540; [MꢁC2H3O]þ (4) m/z calcd for
C20H17N2: 285.1392, found 285.1392; [MꢁC4H7]þ (20) m/z calcd for
C18H13N2O: 273.1022, found 273.1026; [MꢁC5H8N]þ 246(14) m/z
calcd for C17H12NO: 246.0913, found 246.0922; [MꢁC5H9N2]þ (20)
m/z calcd for C17H11O: 231.0804; found 231.0807; [MꢁH]þ 327(20),
C16H11Nþꢂ: 217(10), C16H1þ0ꢂ: 202(7), C15Hþ9 : 189(5).
The ESI spectra were recorded with a UHR-Q-TOF maXis (Bruker
Daltonik GmbH, Bremen, Germany) mass spectrometer in positive
electrospray mode. All samples were injected (3
mL/min) with
a Harvard syringe pump. The capillary voltage was set to 4.0 kV.
The desolvation temperature was 180 ꢀC. The desolvation gases
were delivered at 4.0 L/min. For MS/MS after selection of the ap-
propriate precursor ion, nitrogen was used as collision gas and the
gas cell was maintained between 5 and 65 eV.
Starting trifunctional aminonaphthols were synthetized
Acknowledgements
according to literature methods: 34 and 6.5
The authors thank the Hungarian Research Foundation (OTKA
No. K-75433) and TAMOP-4.2.1/B-09/KONV-2010-0005 and the
4.2. Synthesis of 4
ꢀ
Deutsche Akademische Austauschdienst (DAAD), project-ID
50368559, for financial support. I.S. acknowledges the award of
Et3N (0.15 mL, 1.1 mmol) and aqueous glutardialdehyde solution
(25%, 0.42 mL, 1.1 mmol) were added to a solution of 3 (379 mg,
1 mmol) in EtOH (15 mL). The mixture was stirred for 1 day at room
temperature, during which white crystals separated out. The
crystalline product (4) was filtered off, washed with cold EtOH
(2ꢃ5 mL) and recrystallized from iPr2O (10 mL).
ꢀ
a Bolyai Janos Fellowship.
References and notes
1. Arrayas, R. G.; Carratero, J. C. Chem. Soc. Rev. 2009, 38, 1940e1948.
2. Martin, S. F. Pure Appl. Chem. 2009, 81, 195e204.
White crystals, 267 mg (81%), mp: 207e209 ꢀC. 1H NMR
ꢀ
€ €
3. Szatmari, I.; Fulop, F. Curr. Org. Synth. 2004, 1, 155e165.
(600 MHz, CD2Cl2):
d
¼1.73e1.81 (m, 2H, 9-Heq, 8-Hax), 1.92e2.02
ꢀ
€ €
4. Heydenreich, M.; Koch, A.; Klod, S.; Szatmari, I.; Fulop, F.; Kleinpeter, E. Tetra-
hedron 2006, 62, 11081e11089.
5. Csutortoki, R.; Szatmari, I.; Koch, A.; Heydenreich, M.; Kleinpeter, E.; Fulop, F.
Tetrahedron 2011, 67, 8564e8571.
(m, 2H, 10-Hax, 9-Hax), 2.08e2.12 (m, 1H, 10-Heq), 2.17e2.22 (m, 1H,
8-Heq), 4.91 (dd, 1H, J¼9.4, 5.4 Hz, 7a-H), 5.64e5.66 (m, 1H, 10a-H),
5.88 (s, 1H, 15b-H), 6.62 (td, 1H, J¼7.5, 1.1 Hz, 14-H), 6.78e6.82 (m,
2H, 15-H, 12-H), 7.05 (d, 1H, J¼8.9 Hz, 6-H), 7.11 (t, 1H, J¼7.7 Hz, 13-
H), 7.39 (td, 1H, J¼7.6, 0.9 Hz, 3-H), 7.52 (td, 1H, J¼7.4, 1.4 Hz, 2-H),
7.74 (d, 1H, J¼8.9 Hz, 5-H), 7.81e7.85 (t, 2H, J¼8.1 Hz, 4-H, 1-H). 13C
€ €
€
ꢀ
€ €
6. Kuznetsov, V. F. U.S. Patent 7,855,296, 2010.
7. Lopez, S.; Fernandez-Trillo, F.; Midon, P.; Castedo, L.; Saa, C. J. Org. Chem. 2005,
70, 6346e6352.
ꢀ
ꢀ
ꢀ
ꢀ
8. 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.; Nakatsuji, H.; Car-
icato, 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.; Naka-
jima, 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.; Dannenberg, 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.
NMR (150 MHz, CD2Cl2):
d
¼16.9 (C-9), 30.4 (C-10), 31.2 (C-8), 53.8
(C-15b), 81.1 (C-7a), 87.3 (C-10a), 114.1 (C-15c), 116.4 (C-12), 118.8
(C-6), 120.3 (C-14), 122.0 (C-15a), 123.1 (C-1), 123.8 (C-3), 127.3 (C-
2), 128.9 (C-4), 129.0 (C-4a), 129.1 (C-13, C-15), 129.8 (C-5), 132.9 (C-
15d), 150.4 (C-6a), 153.1 (C-11a).
HR-EI-MS formula and RA (%): [M]þ. (100) m/z calcd for
C22H20NO2: 329.1410, found 329.1427; [MꢁOH]þ (92) m/z calcd for
C22H18NO: 312.1388; found 312.1377; [MꢁCHO]þ (5) m/z calcd for
C21H18NO: 300.1383, found 300.1378; [MꢁC2H3O]þ (6) m/z calcd
for C20H16NO: 286.1232, found 286.1238; [MꢁC5H8N]þ 247(20); m/
z calcd for C17H11O2: 247.0754, found 247.0758; [MꢁC5H8NO]þ
(100) m/z calcd for C17H11O: 231.0804, found 231.0807; [MꢁH]þ
328(25), C16H10Oþꢂ: 218(10), C16H1þ0ꢂ: 202(10), C15Hþ9 : 189(24).
9. (a) Hehre, W. J.; Radom, L.; v. Rague Schleyer, P.; Pople, J. Ab Initio Molecular
Orbital Theory; Wiley: New York, NY, 1986; (b) Becke, A. D. J. Chem. Phys. 1993,
98, 1372e1377.
10. SYBYL 7.3; Tripos: 1699 South Hanley Road, St. Louis, MO 63144, USA, 2007.
11. PERCH Solutions Ltd. Kuopio, Finland Laatikainen, R. J. Magn. Reson. 1991, 92,
1e9; Laatikainen, R. QCMP100. MLDC8 QCPE Bull. 1992, 12, 23; Laatikainen, R.;
€ €
Niemitz, M.; Weber, U.; Sundelin, J.; Hassinen, T.; Vepsalainen, J. J. Magn. Reson.
4.3. Synthesis of 7
1996, A120, 1e10; Laatikainen, R.; Niemitz, M.; Malaisse, W. J.; Biesemans, M.;
Willem, R. Magn. Reson. Med. 1996, 36, 359e365.
12. Pihlaja, K.; Liukko-Sipi, S.; Fulop, F.; Bernath, G.; Vainiotalo, P. Rapid Commun.
€ €
ꢀ
To a solution of 6 (264 mg, 1 mmol) in EtOH (15 mL), aqueous
glutardialdehyde solution (25%, 0.42 mL, 1.1 mmol) was added and
the mixture was stirred at room temperature. After 3 h, when TLC
indicated no presence of the starting materials, the reaction mix-
ture was concentrated under reduced pressure. The product was
then isolated by column chromatography (eluent: n-hexane/EtOAc
2:1 v/v) and was crystallized from n-hexane.
Mass Spectrom. 1991, 5, 230e233.
13. Martiskainen, O.; Fulop, F.; Szatmari, I.; Pihlaja, F. Arkivoc 2009, iii, 115e129.
€ €
ꢀ
ꢀ ꢀ
€ €
ꢀ
14. Joutsiniemi, K.; Vainiotalo, P.; Pihlaja, K.; Lazar, L.; Fulop, F.; Bernath, G. Rapid
Commun. Mass Spectrom. 1995, 9, 1035e1037.
ꢀ ꢀ
€ €
ꢀ
15. Joutsiniemi, K.; Vainiotalo, P.; Lazar, L.; Fulop, F.; Bernath, G. Rapid Commun.
Mass Spectrom. 1995, 9, 998e1002.
€ €
ꢀ
ꢀ
16. Vainiotalo, P.; Fulop, F.; Stajer, G.; Bernath, G.; Pihlaja, K. Acta Chem. Scand. 1990,
44, 165e169.
ꢀ
ꢀ
€ €
17. Juhasz, M.; Zalan, Z.; Fulop, F.; Pihlaja, K. Rapid Commun. Mass Spectrom. 2006,
20, 3595e3604.
Beige crystals,141 mg (43%), mp: 197e199 ꢀC.1H NMR (600 MHz,
18. (a) Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209e220; (b) Stewart, J. J. P. J.
Comput. Chem. 1989, 10, 221e264.
19. Becke, A. D. J. Chem. Phys. 1993, 98, 5648e5652.
20. Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785e789.
21. Tomasi, J.; Mennucci, B.; Cammi, R. Chem. Rev. 2005, 105, 2999e3093.
CD2Cl2):
d
¼1.69e1.71 (m, 1H, 9-Heq), 1.72e1.74 (m, 1H, 8-Hax),
1.74e1.79 (m,1H,10-Hax),1.94e1.98 (m,1H, 9-Hax),1.99e2.04 (m,1H,
10-Heq), 2.14e2.19 (m, 1H, 8-Heq), 3.99 (br s, 1H, NH), 4.85 (dd, 1H,
J¼9.4, 4.1Hz, 7a-H), 5.17e5.19 (m,1H,10a-H), 5.78(s,1H,15b-H), 6.37