Synthesis and detailed conformational analysis of new naphthoxazino[2,3-a]benz[c]azepine and naphthoxazino[2,3-a]thieno[3,2-c]pyridine derivatives

Article abstract of DOI:10.1016/j.tet.2017.06.060

New naphth[1,3]oxazino-benzazepines and -thienopyridines were synthesized using a modified Mannich-type synthetic pathway by the reaction of 4,5-dihydro-3H-benz[c]azepine or 6,7-dihydrothieno[3,2-c]pyridine and different substituted aminonaphthols. Reaction conditions were optimized using microwave irradiation, with relatively short reaction times and a temperature of 80 °C. The formation of undesired naphthoxazine by-products made the separation/purification of the products challenging, therefore the reactions were repeated and systematically studied, starting from secondary and tertiary aminonaphthol derivatives, when the isolation of an ortho-quinonemethide structure occurred unexpectedly. Scope and limitations of its formation were also investigated. Conformational studies including ring inversion of a selection of the novel polyheterocycles were performed using NMR methods and supplementary DFT modelling.

Full text of DOI:10.1016/j.tet.2017.06.060

Accepted Manuscript
Synthesis and detailed conformational analysis of new
naphthoxazino[2,3-a]benz[c]azepine and naphthoxazino[2,3-a]thieno[3,2-c]pyridine
derivatives
István Szatmári, Petra Barta, Antal Csámpai, Ferenc Fülöp
PII:
S0040-4020(17)30703-2
10.1016/j.tet.2017.06.060
TET 28825
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 April 2017
Revised Date: 15 June 2017
Accepted Date: 27 June 2017
Please cite this article as: Szatmári Istvá, Barta P, Csámpai A, Fülöp F, Synthesis
and detailed conformational analysis of new naphthoxazino[2,3-a]benz[c]azepine and
naphthoxazino[2,3-a]thieno[3,2-c]pyridine derivatives, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.06.060.
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Synthesis and deAtaCiCleEdPTcEoDnMfoArNmUaStCiRoInPaTl analysis of new
naphthoxazino[2,3-a]benz[c]azepine and naphthoxazino[2,3-
a]thieno[3,2-c]pyridine derivatives
István Szatmári1, Petra Barta1, Antal Csámpai2 and Ferenc Fülöp1,*
1Institute of Pharmaceutical Chemistry and Research Group for Stereochemistry, Hungarian
Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
Fax.: +36-62-545-705; Email: fulop@pharm.u-szeged.hu
2Institute of Chemistry, Eötvös Loránd University, H-1518 Budapest, PO Box 32, Hungary
Abstract
New naphth[1,3]oxazino-benzazepines and -thienopyridines were synthesized using a modified
Mannich-type synthetic pathway by the reaction of 4,5-dihydro-3H-benz[c]azepine or 6,7-
dihydrothieno[3,2-c]pyridine and different substituted aminonaphthols. Reaction conditions were
optimized using microwave irradiation, with relatively short reaction times and a temperature of 80
°C. The formation of undesired naphthoxazine by-products made the separation/purification of the
products challenging, therefore the reactions were repeated and systematically studied, starting from
secondary and tertiary aminonaphthol derivatives, when the isolation of an ortho-quinonemethide
structure occurred unexpectedly. Scope and limitations of its formation were also investigated.
Conformational studies including ring inversion of a selection of the novel polyheterocycles were
performed using NMR methods and supplementary DFT modelling.
Keywords: aminonaphthol; DFT modelling; Mannich reaction; microwave reaction; ortho-
quinonemethide
1

ACCEPTED MANUSCRIPT
Introduction
The Mannich reaction1-3 is an important method to form new C–C bonds. This synthetic
pathway is widely used in the formation of secondary and tertiary amine derivatives and it is a key
step in the syntheses of numerous bioactive molecules and complex natural products.4,5 In one of
the special variations of the modified Mannich reaction (Figure 1), 1- and 2-naphthols are applied as
electron-rich aromatic compounds.6,7
The synthesis of new heterocycles is one of the most important areas of application of
Mannich bases bearing two or more functional groups.6,7 In previous papers, the synthesis and
conformational studies of naphth[1,2-e][1,3]oxazino[3,4-c][1,3]benzoxazines,8,9 naphth[1,2-
e][1,3]oxazino[3,4-c]quinazolines,10 naphth[1,2-e][1,3]oxazino[3,2-c]quinazolin-13-ones11 and
naphth[1,2-e][1,3]oxazino[4,3-a]isoquinoline derivatives12 were published.
In our earlier studies, an unexpected reaction between 1-α-aminobenzyl-2-naphthol or 1-
aminomethyl-2-naphthol and 6,7-dimethoxy-3,4-dihydroisoquinoline led to the formation of 9,10-
dimethoxy-naphth[1,2-e][1,3]oxazino[2,3-a]isoquinolines under microwave (MW) irradiation.13 In
the latter syntheses, 1-aminomethyl-2-naphthol and substituted 1-aminobenzyl-2-naphthols were
applied to prepare naphth[1,2-e][1,3]oxazino[2,3-a]isoquinoline derivatives. Mechanistically,
aminonaphthols were proven to be the initiator of the intermediate for the [4+2] cycloaddition
forming the desired pentacycles (Figure 1). A detailed NMR spectroscopic and theoretical study on
the dynamic behavior of these conformationally flexible heterocyclic ring systems confirmed an
unexpected dynamic process between the trans and cis diastereomers.14 Maycock et al. described an
alternative synthesis of naphth[1,2-e][1,3]oxazino[2,3-a]isoquinolines via the copper-mediated
intramolecular α-functionalization of tertiary amines through the oxidative activation of C–H
bonds.15
2

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Modified Mannich-reaction:
R1
NH2
OH
OH
R1-CHO
NH3
+
+
R2
Previous work:
R2
R1 NH2
R2
OH NH2
R1
OH
R1
N
R2
R2
R2
O
N
O
R1
N
- NH3
- NH3
R3
N
This work:
R3
R4
R1
N
R4
OH
OH
R1
R1
N
O
N
O
H
R1
H
N
N
-
-
N
R3
R4
R3
R4
R3
N
R3
R4
S
R1
N
R4
OH
S
OH
R1
R1
N
S
O
N
O
N
H
R1
H
N
-
-
N
R3
R4
R3
R4
Figure 1
Our major aim in this study was to extend this recent reaction, starting from 4,5-dihydro-3H-
benz[c]azepine and 6,7-dihydrothieno[3,2-c]pyridine as cyclic imines and 1-aminobenzyl-2-
naphthols and 2-aminomethyl-1-naphthols (Figure 1).16 In addititon, we also studied the obtained
conformationally flexible ring systems by means of NMR spectroscopy and complementary
theoretical calculations carried out at the B3LYP/6-31 G(d) level of DFT.
In our first experiments, 4,5-dihydro-3H-benz[c]azepine (1) was reacted with aminonaphthol
derivative 2a. The precursor cyclic imine 1 was synthesized using literature methods in four steps
starting from α-tetralone.17,18 The reaction between 1 and 2a was performed in 1,4-dioxane under
3

ACCEPTED MANUSCRIPT
microwave irradiation at 80 °C. Crystallization of the product in MeOH resulted in formation of 3a
in a good yield (Table 1).
Scheme 1. Synthesis of benz[c]azepine derivatives 3a-d and 6b-d
The reaction of 1 and primary aminonaphthol 2b, gave undesired compound 4b. It was
presumed to be a side product19 formed by the reaction of 2b and benzaldehyde (the decomposition
product of 2b). Trans-4b and its acyclic imine form were detected by TLC and by NMR
spectroscopy using the characteristic H-3 chemical shift at 5.64 ppm and at 8.77 ppm. Purification
by column chromatography gave new pentacycle 3b identified as the trans diastereomer 3bA
(Scheme 1) by the NOE interaction between H-7a and the ortho H-2’6’ protons of the phenyl group
attached to position 16. These conditions were then applied to the reactions starting from 2c and 2d.
In these two cases, the NMR spectra recorded for the crude products indicated the presence of the
desired pentacycles 3c and 3d contaminated by naphthoxazines 4c and 4d, respectively. The
protocol based on column chromatography proved to be successful in the separation of 3c and 4c,
but failed for the mixture of 3d and 4d. Since further attempts (e.g. recrystallization) were found to
be ineffecient to separate the desired naphthoxazine, the development of a new synthetic strategy
was needed to isolate 3d in pure form.
To examine the possibility of the extension of the reaction, 2-aminobenzyl-1-naphthols (5b-
d) were also applied as reactants in the annulation reactions. Related results and conditions are
4

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summarized in Table 1. By-products 7b-d20,21 were also detected but the separation process with
7b-d was successful and new derivatives 6b-d were isolated in pure form (Scheme 1).
Table 1. Reaction conditions for the preparation of naphthoxazino-benzazepines (3a-d, 6b-d)
Reaction
time (min)a
30
Conversiond Yielde
Aminonaphthol
Product(s)
D.r.b
-
(%)
(%)
91
77
2a
3aA
3bB
c
3bA
4b
(52%)
4c
(56%)
4d
(55%)
7b
(49%)
7c
(52%)
7d
80
80
40
40
20
40
-
92
91
88
93
88
90
37
34
2b
2c
2d
5b
5c
5d
(48%) (0%)
3cA 3cB
(44%) (0%)
3dA 3dB
(45%) (0%)
6bA 6bB
(44%) (7%)
6cA 6cB
(48%) (0%)
6dA 6dB
c
-
c
f
-
-
g
1:0.16
-
c
-
32
g
1:0.25
-
(39%) (10%) (51%)
a syntheses were achieved at 80 °C using microwave irradiation
b diastereomeric ratio (trans:cis), determined from the 1HNMR spectra of the crude reaction
mixtures
c the minor distereomer could not be detected
d conversion, calculated from the 1HNMR spectra of the crude reaction mixtures
e isolated yields, obtained for the major (A) products
f the desired (A and B) and the by-product (C) could not be separated
g the diastereomers (A and B) could not be separated
Next, 6,7-dihydrothieno[3,2-c]pyridine (8) was chosen as a new representative cyclic imine.
Its synthesis was achieved via a Bischler-Napieralski cyclization starting from 2-thiophen-2-yl-
ethylamine.22 Through the reaction of 8 and 2a, the formation of the desired unsubstituted
naphthoxazine 9a was obtained in good yield (74%, Table 2).
When the synthesis started from aminoarylnaphthols (2b-d or 5b-d; Scheme 2) the results of
the separation process of the pentacycles 9b-d or 10b-d from the naphthoxazines 4b-d or 7b-d
depended on the structure of the initial compound. With the exception of 9c and 9d column
chromatography proved to be successful to provide the desired pentacycles 9b, 10b-d (Table 2) in
pure form. Because of the difficulty with 9c and 9d, an alternative synthetic pathway was needed.
5

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Scheme 2. Synthesis of thieno[3,2-c]pyridine derivatives 9a-d and 10b-d
Table 2. Reaction conditions for the preparation of naphthoxazino-thienopyridines (9a-d, 10b-d)
Reaction
time (min)a
20
Conversiond Yielde
Aminonaphthol
D.r.b
Product(s)
(%)
(%)
-
92
74
2a
2b
9aA
9bB
c
9bA
(42%)
9cA
(44%)
9dA
4b
60
40
40
20
20
20
-
93
90
91
88
92
89
38
(0%) (58%)
9cB 4c
(0%) (56%)
9dB 4d
(0%) (54%)
10bB 7b
c
f
-
-
2c
2d
5b
5c
5d
c
f
-
-
(46%)
10bA
g
1:0.30
-
(34%) (10%) (56%)
c
10cA
(49%)
10dA
10cB
(0%) (51%)
10dB 7d
7c
-
34
g
1:0.33
-
(36%) (12%) (52%)
a syntheses were achieved at 80 °C using microwave irradiation
b diastereomeric ratio (trans:cis), calculated from the 1HNMR spectra of the crude reaction mixtures
c the minor distereomer could not be detected
d conversion, calculated from the 1HNMR spectra of the crude reaction mixtures
e isolated yields, obtained for the major (A) products
f the desired (A and B) and the by-product (C) could not be separated
g the diastereomers (A and B) could not be separated
6

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It is important to mention that the formation of two diastereomers is possible in all cases.
Therefore, the diastereomeric ratios were examined in the crude reaction mixture. The formation of
the minor diastereomers 6bB, 6dB, 10bB and 10dB could only be detected when the reaction was
performed with 5b or 5d as aminonaphthol starting materials (Tables 1 and 2). It can be concluded
that the diastereoselectivity of the reaction depends on the steric effect of the aromatic ring at
position 14 or 16 and on the position of annulation of the naphthyl ring.
S
R1
H
H
O
N
N
R2
S
M.W. 80°C
+
OH
N
1,4-dioxane
8
i
2b
11
9bA + 4b
R1 = H; R2 = H : 2b
R1 = H; R2 = -CH2-Ph : 11
R1 = Me; R2 = -CH2-Ph : 12
ii
9bA
9bA
iii
12
Scheme 3. Synthesis of 9bA starting from aminonaphthol derivatives 2b, 11 and 12
Since the separation of 3d, 9c and 9d from by-products 4c-d failed, the development of an
alternative synthetic pathway was necessary. The synthesis of 9bA was chosen as a model reaction
and 2b19 as primary, 1123 as secondary and 1215 as tertiary aminonaphthol derivatives, while 8 was
selected as a cyclic imine (Scheme 3). The reason for selecting secondary and tertiary
aminonaphthols as starting materials was that the formation of the naphthoxazine side products was
not expected. In our systematic investigation, the highest conversion in the reaction of 8 with
different aminonaphthols (2b, 11 and 12) was found for i, albeit with the formation of byproduct 4b
in about 55%. The transformation of 12 (iii) proved to be better, because a conversion of 70% was
measured in 60 min. In contrast, secondary aminonaphthol 11 gave a conversion of about 60% after
an extended reaction time of 200 min (Figure 2).
7

ACCEPTED MANUSCRIPT
Figure 2
According to these observations (Figure 2), the selection of tertiary aminonaphthols as
starting compounds and an optimal reaction time of 60 min appeared to be satisfactory.
Accordingly, the synthesis of the missing derivatives 3d, 9c and 9d was planned by reacting
aminonaphthols 13, 14 and cyclic imines 1 or 8. The initial tertiary aminonaphthol 13 was
synthesized from 2-naphthol (15), 1-naphthaldehyde (16) and morpholine, while the synthesis of 14
was achieved by mixing 15 with 2-naphthaldehyde and N-benzylmethylamine (17). When cyclic
imines 1 or 8 and tertiary aminonaphthols 13 or 14 were reacted under microwave irradiation, the
desired products 3d, 6c and 6d were isolated by a simple crystallization in MeOH (Scheme 4). The
NMR spectra of the crude reaction mixtures did not show the presence of the minor (cis)
diastereomers (3dB, 9cB, 9dB), which supports the diastereoselectivity of the reaction.
8

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Scheme 4. Synthesis of 3dA, 9cA and 9dA starting from tertiary aminonaphthols 13 and 14
Scheme 5. The formation of compound 19
As mentioned, the preparation of 9cA was achieved by using tertiary aminonaphthol 13
synthesized from 2-naphthol (15), 1-naphthaldehyde (16) and morpholine. Initially, the synthesis of
9cA was attempted by the reaction of 6,7-dihydrothieno[3,2-c]pyridine (8) and 18. For the synthesis
of this latter compound, 15, 16 and 17 were reacted (neat, 70 °C). The characteristic spot that
formed according to TLC, was isolated. The NMR spectra of the product isolated by column
chromatography adequately supported that this condition did not lead to the expected tertiary
aminonaphthol derivative 18 (Scheme 5). The structure of the formed compound was proven to be
19b that is the formal hydrate of ortho-quinonemethide (oQM) 19a. The class of oQMs has
previously been investigated as exciting short-lived intermediates. They were usually used to
explain reaction pathways, and the difficulty of their isolation was also assessed.24,25
9

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Scheme 6. Proof of the reactivity of 19
To test the reactivity of 19b, it was reacted with representative cyclic imines 1 and 8.
Reactions were performed at 80 °C under MW irradiation and the desired compounds (3cA and
9cA) formed in short reaction times were isolated in high yields (Scheme 6). Their formation can be
mechanistically interpreted by the transformation of 19b to 19a followed by cycloaddition with
cyclic imines 1 or 8.13 The NMR spectra of the crude products supported the diastereoselectivity of
the reaction.
As it was shown the reaction of 15 as the electron-rich aromatic compound, 16 as the
aldehyde and 17 as the amine component afforded 19b. This urged us to start a systematic
investigation to explore the scope and limitations of the synthesis of 19b analogues. Scheme 7
summarizes the structures of products from the reactions of various amine components with 15 and
16.
10

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Scheme 7. Extension of the amine scope to form oQMs
First, the effect of N-benzylmethylamine on the formation of 19b was examined.
Mechanistically, if an oQM structure is formed, the amine component does become incorporated
into the product; rather, it acts as a promoter. Amines with similar basicity such as piperidine,
pyrrolidine, morpholine and dibenzylamine were evaluated. Under the conditions used (neat, 70
°C), secondary amines, with the exception of dibenzylamine gave the expected new aminonaphthol
derivatives 13, 20 and 21. Of related amines, N-methylphenethylamine gave 22 as a single product,
while N-methylaniline proved to be unreactive. A similar failed test included triethylamine, a
tertiary amine (Scheme 7).
11

ACCEPTED MANUSCRIPT
Scheme 8. Extension of the aldehyde scope to form oQMs
In the next step the aldehyde component 16 was changed. Benzaldehyde and 2-
naphthaldehyde were both tested but they both gave the classical 3-component products 2315 and
14. By the application of p-anisaldehyde and p-nitrobenzaldehyde, the effect of an electron donating
and an electron withdrawing group were also examined. The formation of an oQM structure was
again not observed and 24 and 25 were isolated as single products (Scheme 8).
The NMR data (listed in the Experimental section) are consistent with the structures of the
novel compounds. However, the characteristics of the stereostructures of novel pentacycles 3, 6, 9
and 10 including their relative configuration and conformation must be commented on. The trans
structure of compounds of type A was unambiguously evidenced by the NOESY cross peaks
revealing interaction between the oxazine proton of the NCHO group (3A: H-7a; 6A: H-15b; 9A
and 10A: H-14a) and the proximal protons of the attached aryl substituent. Accordingly, the
characteristic NOEs detected between the two oxazine protons of the isolated pentacycles (6bB,
6dB, 10bB and 10dB) refer to their relative cis position on the fused heterocyclic skeleton.
In order to obtain information about the conformation and possible ring inversions of the
pentacycles, we undertook a comparative DFT analysis of representative fused benzazepines
(structures 3bA, 3bB, 6bB, 9bA, 9bB and 10bB) carried out by B3LYP functional26 using 6-
31G(d) as basis set27 (Tables 3 and 4, Figures 3, 4 and 5). For benzazepine models, geometry
optimization identified three minima on the potential energy surface (PES). These correspond to
ring conformers connected by three saddle points representing transition states (TSs) of the
inversions of the partially saturated azepine ring (Figure 4). The TS structures were localized by
means of the QST2 method28. In case of 3bA, conformer 3bA_I was found to be the global
minimum. It features a chair-shaped azepine ring carrying H-14B, H-13A, H-12B and O-7 atoms in
axial position with C-14 in the tip and pyramidal N-15 atom as an additional stereogenic center.
12

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The relative energy (Table 3) calculated for diastereomer 3bA_II incorporating the azepine ring
with boat conformation indicates its slightly decreased population relative to that of 3bA_I in a
ternary equilibrium. The local minimum represented by 3bA_III, containing a boat-shaped azepine
ring with opposite sign of bending, seems to have a minimum share in the conformer population, as
suggested by its relative energy (Table 3). It is of pronounced importance that at room temperature
the calculated low activation energies (Table 3) refer to rapid interconversion between the three
components expected to produce time-average spectra under the applied conditions of the NMR
measurements. This view gains support from the fact that the multiplets originated from the protons
1
of the skeletal (CH2)3 chain appear as relatively broadened signals in the H-NMR spectra of
pentacycles 3A and 6A. Thus, theoretical NMR spectra were generated by the GIAO method29 at
the B3LYP/6-311+G(2d,p) level of theory30 for each component of the assumed equilibrium (Table
3). The best match of the measured and calculated chemical shifts of H-7a, H-16, H-14AB, H-13AB
and H-12AB protons (see Table 3), in line with the relative energetics, indicates that 3bA_I is
unambiguously the dominant one in the mixture of the three conformers present in the DMSO-d6
solution subjected to NMR experiments.
1
Table 3. Diagnostic H NMR shifts (experimental and calculated) and calculated relative energeticsa along with activation barriersa
of the appropriate interconversions between the possible conformers of selected model benzazepines 3bA, 3bB and 6bB
3bA_I
3bA_II 3bA_III
3bB_I
3bB_II 3bB_III
6bB_I
6bB_II 6bB_III
Erel = 0
Erel
0.6
=
Erel = 2.8
Erel
2.2
=
Erel
0.9
=
Erel = 0
Erel
2.2
=
Erel
1.9
=
Erel = 0
E‡(I→II) = 7.2
E‡(III→II) = 5.1
E‡(III→II) = 7.8
E‡(II→III) = 4.8
E‡(I→III) = 9.9
E‡(II→I) = 7.2
E‡(III→I) = 9.2
E‡(I→II) = 7.0
E‡(III→I) = 9.3
No. of
atoms
H-7a
Exp.
1H
5.69
5.55
3.30-
3.18
1.94
1.87
3.03
2.89
Calcd.
Calcd.
Exp.
Calcd.
Calcd.
Calcd.
1H
No. of Exp.
Calcd.
Calcd.
Calcd.
1H
Calcd.
1H
1H
1H
1H
-
1H
1H
atoms
H-15b
H-7
1H
1H
1H
5.75
5.50
3.55
3.23
1.93
2.03
3.27
2.65
6.30
5.51
3.56
2.72
1.74
2.44
2.37
3.96
5.92
5.69
3.21
3.64
2.09
1.64
4.01
2.61
6.11
6.57
3.36
2.29
1.76
1.65
3.70
2.65
6.58
6.64
3.10
2.56
1.36
1.48
2.30
3.94
5.80
5.76
2.94
2.69
1.50
1.23
3.89
2.42
5.99
5.44
2.51
2.45
1.68
1.33
3.22
2.78
6.42
6.43
3.34
2.54
1.81
1.72
3.75
2.71
6.92
6.44
3.20
2.81
1.40
1.42
2.31
3.85
6.00
5.42
2.70
2.65
1.71
1.27
3.68
2.54
H-16
-
-
-
-
-
-
-
H-14B
H-14Α
H-13B
H-13Α
H-12B
H-12Α
H-9B
H-9Α
H-10B
H-10Α
H-11B
H-11Α
a in kcal/mol
13

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Table 4. Diagnostic 1H NMR shifts (experimental and calculated) and calculated relative energeticsa along with activation barriersa of the
appropriate interconversions between the possible conformers of selected model thienopyridines 9bA, 9bB and 10bB
No. of
atoms
9bA_I
9bA_II
Erel = 0.6
9bB_I
Erel = 1.5
9bB_II
Erel = 0
10bB_I
Erel = 1.7
10bB_II
Erel = 0
E‡(II→I) = 6.9
Calcd.
1H
Erel = 0
E‡(I→II) = 7.2
E‡(II→I) = 6.4
No. of Exp.
Calcd.
Exp.
Calcd.
No. of
atoms
H-14a
H-7
H-5B
H-5Α
H-4B
H-4Α
Exp.
1H
5.63
4.98
2.95-
2.85
Calcd.
1H
Calcd.
Calcd.
atoms
H-14a
H-7
1H
1H
1H
-
1H
1H
1H
5.61
5.25
3.15
3.27
2.91
3.05
5.72
5.47
3.05
3.44
2.87
3.12
5.84
5.70
3.28
3.94
3.55
3.00
6.06
6.64
3.16
2.20
2.64
2.84
5.70
5.02
3.10
2.82
2.87
2.65
6.49
6.41
3.20
2.46
2.70
2.86
5.82
5.06
3.00
2.93
2.85
2.68
-
-
-
-
H-5B
H-5Α
H-4B
H-4Α
2.80-
2.71
-
a in kcal/mol
Figure 3: Relative (and, consequently, absolute) configurations of the most favored conformers of pentacycles 3bA/B,
6bA/B, 9bA/B and 10bA/B (arbitrarily selected enantiomers) established by combined NMR methods and
complementary DFT modelling studies (cf. Relative energetics of the particular confomers listed in Tables 3 and 4.)
As indicated earlier, cis-isomer 3bB could not be isolated and characterized. Therefore, in
addition to its calculated data, the measured and theoretical chemical shifts obtained for detectable
pentacycle 6bB, comprising the same structural fragments, are also listed in Table 3. In accord with
the relative energetics, the comparison of the aforementioned experimental and calculated chemical
shift values suggests that 3bB_III and 6bB_III, with boat-shaped azepine ring and inverted N-15
(in 3bB_III)/N-8 (in 6bB_III) stereogenic centers, can be stated as the most populated components
in the assumed ternary equilibria. These equilibria involve the three conformers (3bB_I,II,III and
6bB_I,II,III, for 3bB and 6bB, respectively) identified on the appropriate PES (cf. Figure 4). It is
noteworthy that conformers 3bB_I and 6bB_I, featuring bridgehead nitrogen with retained
configuration and chair-shaped azepine ring with stereochemical characteristics identical to those
found in stable 3bA_I, represent the least populated local minima. Additionally, according to the
calculated relative energy data, conformers 3bB_II and 6bB_II, containing bridgehead nitrogen
14

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with retained configuration and boat-shaped azepine ring, have a small, but somewhat larger share
in the conformational equilibria than do 3bB_I and 6bB_I, respectively. It must also be pointed out
that at room temperature the calculated low barriers allow fast interconversions between these
conformers taking place by ring flips and inversion of the bridgehead nitrogen atom (Figure 4).
3bA_III
3bA_II
3bA_TS (II,III)
3bA_TS (I,III)
3bA_TS (I,II)
3bA_I
3bB_II
3bB_TS (II,III)
3bB_IIII
3bB_TS (I,II)
3bB_TS (I,III)
3bB_I
Figure 4. Optimized structures of the conformers and the corresponding transition states involved in ternary equilibria
assumed for trans and cis isomer models 3bA and 3bB, respectively.
15

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9bA_I
9bA_TS (I,II)
9bA_II
9bB_I
9bB_II
9bB_TS (I,II)
Figure 5. Optimized structures of the conformers and the corresponding transition states involved in binary equilibria
assumed for trans and cis isomer models 9bA and 9bB, respectively.
Optimization processes searching for stationary points on the PES representing local minima
and transition states were also conducted at the B3LYP/6-31G(d) level of theory for selected
thienopyridines (9bA, undetectable 9bB and isolated 10bB, Figure 5). For these models, the
calculations identified two conformers containing a tetrahydropyridine ring adopting a half-chair
conformation of opposite helicity connected by a TS. This represents a relatively low energy barrier
allowing their interconversion to take place rapidly at room temperature by ring-flip coupled with
simultaneous nitrogen inversion (Table 4). In the case of trans isomer 9bA, conformer 9bA_I was
found to be somewhat more stable than 9bA_II. This is a sterically more congested isomer in which
the 5-CH2 group is situated in the proximity of the bulky phenyl substituent. Accordingly, referring
1
to the relative shares in the conformational equilibrium, the diagnostic H chemical shift values
calculated for 9bA_I match better the experimental data than do the analogous values obtained for
9bA_II (Table 4). On the other hand, for cis isomers 9bB and 10bB, the modelling studies revealed
that conformers 9bB_II and 10bB_II, both containing the phenyl and 5-CH2 groups in the oppsite
faces of the heterocyclic skeleton, must be considered as the major components in the
conformational equilibria 9bB_Iꢀ9bB_II and 10bB_Iꢀ10bB_II, repectively. This view is
convincingly supported by comparison of the diagnostic 1H chemical shifts measured and calculated
for the appropriate conformer pairs (Table 4).
In summary, it can be concluded that in the most stable conformers of the investigated
model pentacycles the phenyl and, in general, the aryl group and the N-CH2 group are situated on
16

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the oppsite faces of the heterocyclic skeletons characterized by the relative configurations of the
carbon and nitrogen stereogenic centers as presented on Figure 3.
Conclusion
By the reaction of 4,5-dihydro-3H-benz[c]azepine or 6,7-dihydrothieno[3,2-c]pyridine and
different substituted aminonaphthols, a new modified Mannich-type synthetic pathway was applied
to form naphth[1,3]oxazino-benzazepines and –thienopyridines. By carrying out the reactions under
microwave irradiation at 80 °C, the products were formed in short reaction times. The conversion
and the diastereomeric ratio was monitored by crude product NMR spectra in all cases. Because of
the formation of the undesired naphthoxazine by-products, separation and purification failed in
some cases therefore a new strategy was needed for the synthesis of 3dA, 9cA and 9dA wherein the
reactions were performed starting from the corresponding tertiary aminonaphthol derivatives.
During the preparation of the initial tertiary aminonaphthols, the unexpected formation of 19
occurred. A systematic study was started to probe the reactivity of 19 and investigate the scope and
limitations of the generation of an ortho-quinonemethide structure. NMR conformational studies
and theoretical calculations were also performed that corroborated the experimental results.
Experimental
1H and 13C NMR spectra were recorded in CDCl3 or DMSO solutions in 5 mm tubes, at
room temperature, with a Bruker spectrometer at 500 (1H) and 125 (13C) MHz, with the deuterium
signal of the solvent as the lock and TMS as internal standard. In the characterization of the
1
compounds, the H- and 13C NMR signals originated from the Ph, 1-Nph and 2-Nph groups
attached to the heterocyclic skeletons or the amine moiety are assigned to the atoms referred to as
H-1’, H-2’, C-1’, C-2’ and H-1”, H-2”, C-1”, C-2”, etc.
Melting points were determined on a Hinotek X-4 melting point apparatus. Elemental
analyses were performed with a Perkin-Elmer 2400 CHNS elemental analyser. Merck Kieselgel
60F254 plates were used for TLC. The microwave reactions were performed with a CEM Discover
SP microwave reactor.
The starting compounds 1,17,18 2a-d,21 5b-d,21 8,22 11,23 1215 and 2315 were synthesized
using literature methods.
17

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General procedure for the synthesis of naphth[1,2-e][1,3]oxazino[2,3-a]benz[c]azepines (3a-c,
6b-d) and naphth[1,2-e][1,3]oxazino[2,3-a]thienopyridines (9a, 9b, 10b-d) starting from
primary aminonaphthols (2a-c and 5b-d)
A mixture of the appropriate aminonaphthol hydrochloride (0.44 mmol), 4,5-dihydro-3H-
benz[c]azepine (1, 0.4 mmol) or 6,7-dihydrothieno[3,2-c]pyridine (8, 0.4 mmol) and Et3N (83 uL,
0.6 mmol) in 1,4-dioxane (5 mL) was placed in a 10 mL reaction vial and heated in a CEM
microwave reactor under the conditions given in Table 1. The solvent was then evaporated under
reduced pressure and the residue purified by column chromatography (n-hexane–ethyl-acetate).
Naphth[1,2-e][1,3]oxazino[2,3-a]benz[c]azepine (3a)
Column chromatography; eluent: n-hexane:EtOAc (2:1; Rf = 0.75), crystallized from n-hexane (5
mL). Mp: 155-157 °C. Light yellow powder. Yield: 93 mg (77 %). 1H NMR (DMSO-d6, 500 MHz):
7.86 (d, J = 7.8 Hz, 1H, H-4), 7.77 (d, J = 8.9 Hz, 1H, H-5), 7.66 (d, J = 7.8 Hz, 1H, H-1), 7.49 (t, J
= 7.8 Hz, 1H, H-2), 7.37 (t, J = 7.8 Hz, 1H, H-3), 7.24 (t, J = 7.3 Hz, 1H, H-10), 7.15 (d, J = 8.9 Hz,
1H, H-6), 7.13 (t, J = 7.3 Hz, 1H, H-9), 7.11 (d, J = 7.3 Hz, 1H, H-11), 7.02 (d, J = 7.3 Hz, 1H, H-
8), 6.14 (s, 1H, H-7a), 4.51 (d, J = 16.1 Hz, 1H, HA-16), 4.01 (d, J = 16.1 Hz, 1H, HB-16), 3.34
(overlapped by the HDO signal of the solvent, thus assigned by HQSC measurement, HA-14), 3.17-
3.14 (m, 1H, HB-14), 3.05-3.03 (m, 1H, HA-12), 2.92-2.89 (m, 1H, HB-12), 1.95-1.91 (m, 1H, HA-13
1.77-1.73 (m, 1H, HB-13); 13C NMR (DMSO-d6, 125 MHz): 153.6 (C-6a); 142.8 (C-7b), 136.0 (C-
11a), 133.1 (C-16b), 131.2 (C-8), 130.1 (C-11), 129.5 (C-4a), 129.2 (C-4), 129.4 (C-9), 128.5 (C-5),
127.1 (C-2), 126.4 (C-10), 123.9 (C-3), 122.1 (C-1), 118.6 (C-6), 112.0 (C-16a), 92.9 (C-7a), 53.3
(C-14), 50.3 (C-16), 34.9 (C-12), 26.3 (C-13). Anal. calcd. for C21H19NO (301.38): C, 83.69; H,
6.35; N, 4.65. Found: C, 83.73; H, 6.32; N, 4.66.
(7aS*,16R*)-16-Phenylnaphth[1,2-e][1,3]oxazino[2,3-a]benz[c]azepine (3bA)
Column chromatography; eluent: n-hexane:EtOAc (2:1; Rf = 0.80), crystallized from n-hexane (5
1
mL). Mp: 140-143 °C. White powder. Yield: 56 mg (37%). H NMR (DMSO-d6, 500 MHz): 7.88
(d, J = 7.8 Hz, 1H, H-4), 7.85 (d, J = 8.9 Hz, 1H, H-5), 7.34-7.31 (m, 5H, H-(1-3) and H-3’,5’),
7.29 (t, J = 7.5 Hz, 1H, H-4’), 7.27 (d, J = 7.5 Hz, 2H, H-2’6’), 7.24 (t, J = 7.3 Hz, 1H, H-10), 7.19
and 7.18 (two partly overlapping ds, J = 8.9 Hz and 7.3 Hz, resp., 2H, H-6 and H-11), 7.16 (d,
J=8.9 Hz, 1H, H-13), 7.11 (t, J=7.3 Hz, 1H, H-9), 6.92 (d, J=7.3 Hz, 1H, H-8), 5.69 (s, 1H, H-7a),
5.55 (s, 1H, H-16), 3.30-3.18 (m, 2H, HA-14 and HB-14), 3.05-3.02 (m, 1H, HB-12), 2.91-2.88 (m,
1H, HA-12), 1.96-1.93 (m, 1H, HA-13), 1.89-1.85 (m, 1H, HB-13); 13C NMR (DMSO-d6, 125 MHz):
18

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153.2 (C-6a); 143.6 (C-1’), 142.3 (C-7b), 135.8 (C-11a), 132.8 (C-16b), 130.9 (C-8), 130.1 (C-11),
129.7 (C-2’,6’), 129.5 (C-5), 129.4 (C-9), 129.3 (C-4a), 129.0 (C-4), 128.6 (C-3’,5’), 127.8 (C-4’),
127.0 (C-2), 126.5 (C-10), 123.9 (C-3), 123.4 (C-1), 118.9 (C-6), 112.9 (C-16a), 90.5 (C-7a), 64.9
(C-16), 52.7 (C-14), 34.4 (C-12), 28.9 (C-13). Anal. calcd. for C27H23NO (377,48): C, 85.91; H,
6.14; N, 3.71. Found: C, 85.87; H, 6.17; N, 3.73.
(7aS*,16R*)-16-Naphth-1-yl-naphth[1,2-e][1,3]oxazino[2,3-a]benz[c]azepine (3cA)
Column chromatography; eluent: n-hexane:EtOAc (4:1; Rf = 0.80), crystallized from n-hexane (4
1
mL). Mp: 225-227 °C. White powder. Yield: 58 mg (34%). H NMR (DMSO-d6, 500 MHz): 8.50
(d, J = 8.3 Hz, 1H, H-8’), 7.99 (d, J = 8.0 Hz, 1H, H-5’), 7.90, 7.89 and 7.88 (three partly
overlapping ds, J = 8.9 Hz, 7.8 Hz and 8.0 Hz, 3H, H-5, H-4 and H-4’), 7.68 (t, J = 8.0 Hz, 1H, H-
7’), 7.59 (t, J = 8 Hz, 1H, H-6’), 7.34 (t, J = 8.0 Hz, 1H, H-3’), 7.30 (t, J = 8 Hz, 1H, H-3), 7.25 and
7.23 (partly overlapping d and t, J = 8.9 Hz and 7.9 Hz, resp., 2H, H-6 and H-2), 7.19 (t, J = 7.3 Hz,
1H, H-9), 7.17 (d, J = 8.9 Hz, 1H, H-13), 7.15 and 7.13 (partly overlappin d and t, J = 7.9 Hz and
7.3 Hz, resp., 2H, H-1 and H-11), 7.05 (t, J = 7.3 Hz, 1H, H-10), 6.94 (d, J = 8.0 Hz, 1H, H-2’),
6.91 (d, J = 7.3 Hz, 1H, H-8), 6.21 (s, 1H, H-16), 5.92 (s, 1H, H-7a), 3.60-3.56 (m, 1H, HA-14 ),
3.40.3.36 (m, 1H, HB-14), 3.02-2.98 (m, 1H, HA-12), 2.86-2.82 (m, 1H, HB-12), 2.02-1.98 (m, 1H,
13
HA-13), 1.94-1.90 (m, 1H, HB-13); C NMR (DMSO-d6, 125 MHz): 153.7 (C-6a), 142.2 (C-7b),
138.8 (C-1’), 135.5 (C-11a), 134.3 (C-4’a), 132.4 (C-16b), 131.6 (C-8’a), 131.0 (C-8), 130.1 (C-
11), 129.6 (C-5), 129.5 (C-4a), 129.3 (C-9), 129.1 (two coalesced lines, C-4 and C-5’), 128.9 (C-
2’), 128.8 (C-4’), 127.0 (C-2), 126.9 (C-7’), 126.5 (C-10), 126.4 (C-6’), 125.7 (C-3’), 123.8 (C-3),
123.3 (C-1), 118.9 (C-6), 112.2 (C-16a), 90.7 (C-7a), 62.3 (C-16), 52.1 (C-14), 34.2 (C-12), 29.0
(C-13). Anal. calcd. for C31H25NO (427.54): C, 87.09; H, 5.89; N, 3.28. Found: C, 87.02; H, 5.93;
N, 3.31.
(7aS*,16R*)-16-Phenylnaphth[2,1-e][1,3]oxazino[2,3-a]benz[c]azepine (6bA)
1H NMR (DMSO-d6, 500 MHz): 8.18-8.15 (m, 1H,. H-1), 7.87-7.84 (m, 1H, H-4), 7.55-7.52 (m,
2H, H-2 and H-3), 7.38 (d, J = 8.8 Hz, 1H, H-5), 7.34 (t, J = 7.8 Hz, 2H, H-3’,5’), 7.23 (d, J = 7.7
Hz, 1H, H-12), 7.30-7.28 (m, 3H, H-2’,6’ and H-4’), 7.20 (t, J = 7.7 Hz, 1H, H-13), 7.03-7.00 (m,
1H, H-14), 6.92 (d, J = 8.0 Hz, 1H, H-15), 6.85 (d, J = 8.8 Hz, 1H, H-6), 6.16 (s, 1H, H-15b), 4.92
(s, 1H, H-7), 3.23-3.19 (m, 1H, H-9A), 3.13-3.09 (m, 1H, H-9B), 2.99 (t, J =5.9 Hz, 2H, H-11A and
H-11B), 1.88-1.84 (m, 1H, H-10A) 1.70-1.66 (m, 1H, H-10B); 13C NMR (DMSO-d6, 125 MHz):
148.9 (C-16a), 143.2 (C-1’), 141.6 (C-15a), 137.2 (C-11a), 133.5 (C-4a), 130.3 (C-12), 129.6 (C-
2’,6’), 129.1 (C-15), 128.9 (two coalesced lines, C-3’,5’ and C-13), 128.2 (C-4), 128.1 (C-4’), 127.3
19

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(C-6), 126.8 (C-2), 126.3 (C-14), 126.2 (C-3), 124.6 (C-16b), 121.5 (C-1), 120.0 (C-5), 117.5 (C-
6a), 89.9 (C-15b), 62.0 (C-7), 51.8 (C-9), 35.1 (C-11), 26.2 (C-10).
(7aS*,16S*)-16-Phenylnaphth[2,1-e][1,3]oxazino[2,3-a]benz[c]azepine (6bB)
Characteristic signals assigned for the minor component in the complex spectra registered of a
mixture of 6bA and 6bB: 1H NMR (DMSO-d6, 500 MHz): 8.07-8.04 (m, 1H, H-1), 7.32 (d, J = 8.8
Hz, 1H, H-5), 6.74 (d, J = 8.8 Hz, 1H, H-6), 5.99 (s, 1H, H-15b), 5.44 (s, 1H, H-7), 3.24-3.20 (m,
1H, H-11A) 2.80-2.76 (m, 1H, H-11B), 2.53-2.49 (m, 1H, H-9A) and 2.46-2.42 (m, 1H, H-9B), 1.70-
13
1.66 (m, 1H, H-10A), 1.35-1.31 (m, 1H, H-10B); C NMR (DMSO-d6, 125 MHz): 149.7 (C-16a),
121.6 (C-1), 121.0 (C-6), 120.1 (C-5), 93.2 (C-15b), 66.8 (C-7), 43.9 (C-9), 30.1 (C-11), 21.6 (C-
10).
(7aS*,16R*)-16-Naphth-1-yl-naphth[2,1-e][1,3]oxazino[2,3-a]benz[c]azepine (6cA)
Column chromatography; eluent: n-hexane:EtOAc (6:1; Rf = 0.75), crystallized from cold n-hexane
1
(3 mL). Yellow powder. Mp: 149-152 °C. Yield: 55 mg (32%). H NMR (DMSO-d6, 500 MHz):
8.34 (d, J = 7.9 Hz, 1H, H-8’), 8.19-8.16 (m, 1H, H-1), 7.93 (d, J = 7.9 Hz, 1H, H-5’), 7.87 and 7.86
(partly overlapping ds, J = 7.7 Hz, 2H, H-4 and H-4’, resp.), 7.54-7.49 (m, 4H, H-2, H-3, H-6’ and
H-7’), 7.41 (t, J = 7.7 Hz, 1H, H-3’), 7.38 (d, J = 8.9 Hz, 1H, H-5), 7.19-7.17 (m, 2H, H-12 and H-
13), 7.11 (d, J = 7.7 Hz, 1H, H-2’), 7.04-7.02 (m, 2H, H-14 and H-15), 6.92 (d, J = 8.9 Hz, 1H, H-
6), 6.14 (s, 1H, H-15b), 5.65 (s, 1H, H-7), 3.43-3.39 (m, 1H, H-9A), 3.24-3.20 (m, 1H, H-9B), 2.95
13
(t, J = 5.9 Hz, 2H, H-11A and H-11B), 1.93-1.89 (m, 1H, H-10A), 1.85-1.81 (m, 1H, H-10B); C
NMR (DMSO-d6, 125 MHz): 149.4 (C-16a), 141.6 (C-15a), 138.8 (C-1’), 137.5 (C-11a), 133.6 (C-
4a), 131.8 (C-8’a), 130.3 (C-12), 129.8 (C-15), 129.4 (C-2’), 129.0 (C-5’), 128.6 (two coalesced
lines, C-4 and C-13), 128.3 (C-4’), 127.1 (C-6), 126.9 (C-4’a), 126.6 (C-7’), 126.4 (C-6’), 126.3 (C-
14), 126.2 (C-2), 126.1 (C-1), 125.4 (C-3’), 125.3 (C-8’), 124.5 (C-16b), 120.2 (C-5), 114.4 (C-6a),
90.3 (C-15b), 63.1 (C-7), 51.8 (C-9), 34.4 (C-11), 27.2 (C-10). Anal. calcd. for C31H25NO (427.54):
C, 87.09; H, 5.89; N, 3.28. Found: C, 87.02; H, 5.93; N, 3.31.
(7aS*,16R*)-16-Naphth-2-yl-naphth[2,1-e][1,3]oxazino[2,3-a]benz[c]azepine (6dA)
1H NMR (DMSO-d6, 500 MHz): 8.21-8.19 (m, 1H, H-1), 7.89, 7.87 and 7.86 (partly overlapping
ds, J = 7.8 Hz for each, 3H, H-4, H-4’ and H-5’), 7.83 (d, J = 7.7 Hz, 1H, H-8’), 7.72 (br s, 1H, H-
1’), 7.56-7.54 (m, 2H, H-2 and H-3), 7.50 (td, J = 7.7 Hz and 1.8 Hz, 1H, H-6’), 7.47 (td, J = 7.7 Hz
and 1.8 Hz, 1H, H-7’), 7.45 (d, J = 7.8 Hz, 1H, H-3’), 7.37 (d, J = 8.9 Hz, 1H, H-5), 7.24 (d, J = 7.6
Hz, 1H, H-12), 7.19 (t, J = 7.6 Hz, 1H, H-13), 6.97 (t, J = 7.6 Hz, 1H, H-14), 6.90 (d, J = 7.6 Hz,
20

ACCEPTED MANUSCRIPT
1H, H-15), 6.88 (d, J = 8.9 Hz, 1H, H-6), 6.25 (s, 1H, H-15b), 5.05 (s, 1H, H-7), 3.29-3.25 (m, 1H,
H-9A), 3.15-3.11 (m, 1H, H-9B), 3.00 (t, J = 5.9 Hz, 2H, H-11A and H-11B), 1.92-1.89 (m, 1H, H-
13
10A), 1.70-1.66 (m, 1H, H-10B); C NMR (DMSO-d6, 125 MHz): 149.0 (C-16a), 141.5 (C-15a),
140.6 (C-2’), 137.3 (C-11a), 133.5 (C-4a), 133.1 (C-4’a), 133.0 (C-8’a), 130.4 (C-12), 128.9 (C-
15), 128.8 (C-13), 128.7 (C-1’), 128.6 (C-4), 128.4 (C-8’), 128.1 (C-4’), 128.0 (C-5’), 127.4 (C-3’),
127.3 (C-6), 126.9 (C-3), 126.6 (two coalesced lines, C-6’ and C-7’), 126.2 (two coalesced lines, C-
2 and C-14), 124.5 (C-16b), 120.0 (C-5), 118.3 (C-6a), 89.9 (C-15b), 62.9 (C-7), 52.0 (C-9), 35.2
(C-11), 26.0 (C-10).
(7aS*,16S*)-16-Naphth-2-yl-naphth[2,1-e][1,3]oxazino[2,3-a]benz[c]azepine (6dB)
Characteristic signals assigned for the minor component in the complex spectra registered of a
1
mixture of 6dA and 6dB: H NMR (DMSO-d6, 500 MHz): 6.77 (d, J = 8.9 Hz, 1H, H-6), 6.05 (s,
1H, H-15b), 5.60 (s, 1H, H-7), 261-2.57 (m, 1H, H-9A), 2.49-2.46 (m, 1H, H-9B), 3.30-3.26 (m, 1H,
13
H-11A), 2.84-2.80 (m, 1H, H-11B); 1.74-1.70 (m, 1H, H-10A) 1.44-1.38 (m, 1H, H-10B); C NMR
(DMSO-d6, 125 MHz): 148.6 (C-16a), 126.7 (C-6), 93.1 (C-15b), 66.8 (C-7), 44.0 (C-9), 30.2 (C-
11), 25.1 (C-10).
Naphth[1,2-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-c]pyridine (9a)
Column chromatography; eluent: n-hexane:EtOAc (2:1; Rf = 0.75), crystallized from n-hexane (5
mL). Light yellow powder. Mp: 161-164 °C. Yield: 87 mg (74%). 1H NMR (DMSO-d6, 500 MHz):
7.82 (d, J = 8.0 Hz, 1H, H-11), 7.69 (two overlapping ds, J = 7.8 Hz and 8.9 Hz, 2H, H-8 and H-12,
resp.), 7.53 (t, J = 7.7 Hz, 1H, H-9), 7.40 (t, J = 7.7 Hz, 1H, H-10), 7.24 (d, J = 5.1 Hz, 1H, H-1),
7.16 (d, J = 5.1 Hz, 1H, H-2), 5.76 (s, 1H, H-14a), 4.76 (d, J =16.3 Hz, 1H, H-7A), 4.35 (d, J =16.3
Hz, 1H, H-7B), 3.51-3.48 (m, 1H, H-5A), 3.16-3.12 (m, 1H, H-4A), 3.08-3.04 (m, 1H, H-4B), 3.03-
13
2.99 (m, 1H, H-5B); C NMR (DMSO-d6, 125 MHz): 151.4 (C-13a), 138.1 (C-3a), 133.3 (C-14b),
131.4 (C-7b), 129.0 (C-11a), 128.7 (C-11), 128.2 (C-12), 126.6 (C-9), 125.6 (C-1), 123.8 (C-2),
123.6 (C-10), 121.1 (C-8), 118.9 (C-13), 111.3 (C-7a), 84.1 (C-14a), 51.0 (C-7), 46.4 (C-5), 25.9
(C-4). Anal. calcd. for C18H15NOS (293.38): C, 73.69; H, 5.15; N, 4.77. Found: C, 73.74; H, 5.11;
N, 4.81.
(7aS*,14R*)-14-Phenylnaphth[1,2-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-c]pyridine
(9bA)
Column chromatography; eluent: n-hexane:EtOAc (20:1; Rf = 0.70), crystallized from cold n-
1
hexane (3 mL). White powder. Mp: 152-154 °C. Yield: 56 mg (38%). H NMR (DMSO-d6, 500
MHz): 7.81 (d, J = 8.0 Hz, 1H, H-11), 7.77 (d, J = 8.9 Hz, H, H-12), 7.69 (d, J = 7.8 Hz, 1H, H-8),
21

ACCEPTED MANUSCRIPT
7.38-7.25 (m, 7H, H-9,10 and H-2’-6’), 7.17 (d, J = 5.1 Hz, 1H, H-2), 7.03 (d, J = 5.1 Hz, 1H, H-1),
5.71 (s, 1H, H-14a), 5.52 (s, 1H, H-7), 3.47-3.44 (m, 1H, H-5A), 3.28-3.24 (m, 1H, H-4A), 3.23-3.19
(m, 1H, H-5B), 3.00-2.96 (m, 1H, H-4B); 13C NMR (DMSO-d6, 125 MHz): 151.8 (C-13a), 142.3 (C-
1’), 138.0 (C-3a), 133.3 (C-14b), 132.4 (C-7b), 129.4 (C-3’,5’), 129.0 (C-11a), 128.6 (C-11), 128.4
(C-2’,6’), 127.5 (C-4’), 126.7 (C-9), 125.8 (C-1), 123.6 (C-2), 123.2 (C-10), 122.6 (C-8), 118.9 (C-
13a), 111.0 (C-7a), 79.0 (C-14a), 62.4 (C-7), 46.9 (C-5), 26.2 (C-4). Anal. calcd. for C24H19NOS
(369,48): C, 78.02; H, 5.18; N, 3.79. Found: C, 78.12; H, 5.10; N, 3.68.
(7aS*,14R*)-14-Phenylnaphth[2,1-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-c]pyridine
(10bA)
1H NMR (DMSO-d6, 500 MHz): 8.00 (d, J = 8.0 Hz, 1H, H-13), 7.84 (d, J = 8.0 Hz, 1H, H-10),
7.49 (t, J = 7.9 Hz, 1H, H-12), 7.46 (t, J = 7.9 Hz, 1H, H-11), 7.43 (d, J = 8.2 Hz, 1H, H-9), 7.38 (d,
J = 5.0 Hz, 1H, H-2), 7.31 (t, J = 7.7 Hz, 2H, H-3’,5’), 7.26-7.22 (m, 3H, H-2’,6’ and H-4’), 7.15
(d, J = 5.0 Hz, 1H, H-1), 7.13 (d, J = 8.2 Hz, 1H, H-8), 5.61 (s, 1H, H-14a), 5.25 (s, H-7), 3.27 (dd,
J = 11.4 Hz and 5.0 Hz, 1H, H-5A), 3.15 (td, J = 11.4 Hz and 5.0 Hz, 1H, H-5B), 3.05 (td, J = 15.9
Hz and 4.2 Hz, 1H, H-4A), 2.91 (dd, J = 15.9 Hz and 5.0 Hz, 1H, H-4B); 13C NMR (DMSO-d6, 125
MHz): 148.9 (C-13b), 143.8 (C-1’), 138.4 (C-3a), 133.7 (C-9a), 133.6 (C-14b), 129.4 (C-2’,6’),
128.6 (C-3’,5’), 128.1 (C-10), 127.7 (C-4’), 127.5 (C-8), 126.8 (C-11), 126.7 (C-1), 125.8 (C-12),
124.5 (C-13a), 124.4 (C-2), 121.6 (C-13), 119.6 (C-9), 113.9 (C-7a), 79.7 (C-14a), 63.5 (C-7), 45.6
(C-5), 26.0 (C-4).
(7aS*,14S*)-14-Phenylnaphth[2,1-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-c]pyridine
(10bB)
Characteristic signals assigned for the minor component in the complex spectra registered of a
1
mixture of 10bA and 10bB: H NMR (DMSO-d6, 500 MHz): 8.19 (d, J = 8.1 Hz, 1H, H-13), 7.78
(d, J = .0 Hz, 1H, H-10), 7.32 (d, J = 8.2 Hz, 1H, H-9), 6.70 (d, J = 8.2 Hz, 1H, H-8), 5.63 (s, 1H,
13
H-14a), 4.98 (s, H-7), 2.95-2.85 (m, 2H, H-5A and H-5B), 2.80-2.71 (m, 2H, H-4A and H-4B); C
NMR (DMSO-d6, 125 MHz): 148.2 (C-13b), 138.1 (C-1’), 137.6 (C-3a), 133.9 (C-14b), 128.2 (C-
10), 126.3 (C-8), 121.5 (C-13), 120.8 (C-9), 87.6 (C-14a), 67.0 (C-7), 46.9 (C-5), 25.1 (C-4).
(7aS*,14R*)-14-Naphth-1-yl-naphth[2,1-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-
c]pyridine (10cA)
Column chromatography; eluent: n-hexane:EtOAc (4:1; Rf = 0.75), crystallized from n-hexane (3
mL). Light yellow powder. Mp: 154-157 °C. Yield: 57 mg (34%). 1H NMR (DMSO-d6, 500 MHz):
8.43 (d, J = 8.0 Hz, 1H, H-13), 8.06 (d, J = 8.1 Hz, 1H, H-5’), 7.97 (d, J = 8.0 Hz, 1H, H-10), 7.90
22

ACCEPTED MANUSCRIPT
(d, J = 7.9 Hz, 1H, H-8’), 7.86 (d, J = 8.0 Hz, 1H, H-4’), 7.67 (t, J = 7.9 Hz, 1H, H-12), 7.59-7.55
(m, 2H, H-11 and H-7’), 7.51 (t, J = 8.1 Hz, 1H, H-6’), 7.48 (d, J = 8.3 Hz, 1H, H-9), 7.38-7.35 (m,
2H, H-3’ and H-1), 7.16 (d, J = 8.3 Hz, 1H, H-8), 7.12 (d, J = 5.1 Hz, 1H, H-2), 6.80 (d, J = 8.0 Hz,
1H, H-2’), 6.02 (s, 1H, H-7), 5.68 (s, H-14a), 3.65 (dd, J=11.4 Hz and 5.0 Hz, 1H, H-5A), 3.26 (td,
13
J=11.4 Hz and 5.0 Hz, 1H, H-5B), 3.07-2.94 (m, 2H, H-4A and H-4B); C NMR (DMSO-d6, 125
MHz): 149.3 (C-13b), 139.2 (C-1’), 138.4 (C-3a), 134.3 (C-4’a), 133.7 (C-9a), 132.7 (C-14b),
132.0 (C-8’a), 129.0 (C-10), 128.6 (C-4’), 128.3 (C-2’), 128.2 (C-8’), 127.5 (C-8), 126.7 (three
coalesced lines, C-6’, C-7’ and C-12), 126.5 (C-2), 126.3 (C-11), 125.0 (C-13), 124.9 (C-3’), 124.5
(C-1), 124.3 (C-13a), 121.7 (C-5’), 119.8 (C-9), 113.5 (C-7a), 79.5 (C-14a), 60.7 (C-7), 45.3 (C-5),
26.0 (C-4). Anal. calcd. for C28H21NOS (419,54): C, 80.16; H, 5.05; N, 3.34. Found: C, 80,24; H,
5,01; N, 3.31.
(7aS*,14R*)-14-Naphth-2-yl-naphth[2,1-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-
c]pyridine (10dA)
1H NMR (DMSO-d6, 500 MHz): 8.06 (d, J = 7.6 Hz, 1H, H-13), 7.92 (d, J = 7.9 Hz, 1H, H-4’),
7.90 (d, J = 7.6 Hz, 1H, H-10), 7.89 (d, J = 7.7 Hz, 1H, H-5’), 7.77 (d, J = 7.7 Hz, 1H, H-8’), 7.54
(t, J = 7.6 Hz, 1H, H-12), 7.67 (dd, J = 7.9 Hz and 1.8 Hz, 1H, H-3’), 7.50-7.46 (m, 4H, H-9, H-11,
H-7’ and H-6’), 7.44 (br s, 1H, H-1’), 7.39 (d, J = 5.4 Hz, 1H, H-2), 7.23 (d, J = 8.8 Hz, 1H, H-8),
7.14 (d, J = 5.4 Hz, 1H, H-1), 5.68 (s, 1H, H-14a), 5.45 (s, 1H, H-7), 3.38 (dd, J=11.5 Hz and 4.2
Hz, 1H, H-5A), 3.22 (td, J = 11.5 Hz and 3.5 Hz, 1H, H-5B), 3.13 (ddd, J = 16.4 Hz, 11.5 Hz and 3.5
13
Hz, 1H, H-4A), 2.97 (d, J = 16.4 Hz, 1H, H-4B), C NMR (DMSO-d6, 125 MHz): 153.8 (C-6a);
149.0 (C-13b), 141.5 (C-2’), 138.4 (C-3a), 133.8 (C-9a), 133.6 (C-14b), 132.7 (two coalesced lines,
C-4’a and C-8’a), 128.4 (two coalesced lines, C-4’ and C-8’), 128.3 (C-3’), 128.1 (C-10), 127.9 (C-
5’), 127.6 (C-8), 126.8 (C-11), 126.7 (C-7’), 126.6 (two coalesced lines, C-1 and C-1’), 126.5 (C-
6’), 124.5 (C-13a), 124.4 (C-2), 121.7 (C-13), 119.7 (C-9), 113.7 (C-7a), 79.7 (C-14a), 63.5 (C-7),
45.7 (C-5), 26.1 (C-4).
(7aS*,14S*)-14-Naphth-2-yl-naphth[2,1-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-
c]pyridine (10dB)
Characteristic signals assigned for the minor component in the complex spectra registered of a
1
mixture of 10dA and 10dB: H NMR (DMSO-d6, 500 MHz): 8.24 (d, J = 7.6 Hz, 1H, H-13), 7.32
(d, J = 8.8 Hz, 1H, H-9), 6.76 (d, J = 8.8 Hz, 1H, H-8), 5.73 (s, 1H, H-14a), 5.17 (s, 1H, H-7), 3.00
(m, 1H, H-5B), 2.83 (m, 2H, H-5A and H-4B) 2.76 (m, 1H, H-4A), 13C NMR (DMSO-d6, 125 MHz):
148.4 (C-13b), 140.1 (C-2’), 137.5 (C-3a), 134.1 (C-14b), 133.0 (C-9a), 126.3 (C-8), 121.5 (C-13),
120.8 (C-9), 120.0 (C-7a), 87.7 (C-14a), 67.2 (C-7), 46.9 (C-5), 25.2 (C-4).
23

ACCEPTED MANUSCRIPT
General procedure for the synthesis of tertiary aminonaphthols (13 and 14)
Morpholine or N-benzylmethylamine (4 mmol) and 1-naphthaldehyde (4 mmol) were mixed and
placed in a 10 mL reaction vial and heated in oil bath at 70 °C for 1 h. Then 4 mmol 2-naphthol was
added and stirred under neat conditions at 70 °C. After 4 h reaction time, the desired tertiary
aminonaphthols were crystallized from methanol (18 mL) and then recrystallized from methanol
(20 mL).
1-(Morpholino(naphthalen-1-yl)methyl)naphthalen-2-ol (13)
Light brown powder. Rf = 0.85 (4:1, n-hexane:EtOAc). Mp.: 152-154 °C. Yield: 1370 mg (85%).
1H NMR (DMSO-d6, 500 MHz): 8.85 (d, J = 8.2 Hz, 1H, H-8’), 7.94 (d, J = 8.2 Hz, 1H, H-5’), 7.82
(d, J = 8.0 Hz, 1H, H-4’), 7.75-7.70 (m, 4H, H-4, H-5, H-2’ and H-7’), 7.69 (d, J = 7.9 Hz, 1H, H-
8), 7.57 (dd, J = 8.2 Hz and 7.6 Hz, 1H, H-6’), 7.40 (t, J = 8.0 Hz, 1H, H-3’), 7.18-7.11 (m, 3H, H-
3, H-6 and H-7), 6.33 (s, 1H, H-9), 3.61 and 3.17 (2xbr s’s 2x2H, H-3”,5”), 2.69 (br s 4H, H-2”,6”)
13C NMR (DMSO-d6, 125 MHz): 156.2 (C-2), 135.5 (C-1’), 133.9 (C-4’a), 133.0 (C-8a), 132.6 (C-
8’a), 129.8 (C-5), 129.6 (C-5’), 129.1 (C-4’), 129.0 (C-4), 128.9 (C-4a), 127.3 (C-7’), 127.1 (C-2’),
126.8 (C-7), 126.3 (C-3’), 126.2 (C-6’), 123.8 (C-8’), 122.8 (C-6), 122.0 (C-8), 120.2 (C-3), 116.6
(C-1), 64.4 (C-9), 66.9 (C-3”,5”), 51.9 (C-2”,6”). Anal. calcd. for C25H23NO2 (369,46): C, 81.27; H,
6.27; N, 3.79. Found: C, 81.33; H, 6.21; N, 3.79.
1-((Benzyl(methyl)amino)(naphthalen-2-yl)methyl)naphthalen-2-ol (14)
Grey powder. Rf = 0.85 (2:1, n-hexane:EtOAc). Mp.: 173-176 °C; Yield: 1122 mg (76%). 1H NMR
(DMSO-d6, 500 MHz): 8.25 and 8.24 (partly overlapping br s and d, J = 8.0 Hz, 2H, H-8’ and H-8,
resp.), 7.91 (d, J = 7.7 Hz, 1H, H-3’), 7.81 (d, J = 7.7 Hz, 1H, H-6’), 7.86 (br s 2H, H-7’ and H-8’),
7.76 and 7.75 (partly overlapping d’s, J = 7.4 Hz and 8.8 Hz, 2H, H-5 and H-4, resp.), 7.50 (t, J =
7.7 Hz, 1H, H-5’), 7.46 (t, J = 7.7 Hz, 1H, H-4’), 7.44 (t, J = 7.4 Hz, 1H, H-7), 7.39 (t, J = 7.8 Hz,
2H, H-3”,5”), 7.33 (d, J = 7.8 Hz, 2H, H-2”,6”), 7.31 (tt, J = 7.8 Hz and 1.5 Hz, 1H, H-4”), 7.24 (td,
J = 7.4 Hz and 1.8 Hz, 1H, H-6), 7.19 (d, J = 8.8 Hz, 1H, H-3), 5.68 (s, 1H, H-9), 3.71 (d, J = 12.9
13
Hz, 1H, H-11A), 3.59 (d, J = 12.9 Hz, 1H, H-11B), 2.15 (s, 3H, H-10); C NMR (DMSO-d6, 125
MHz): 155.2 (C-2), 138.5 (C-1’), 137.6 (C-1”), 133.2 (C-2’a), 132.9 (C-6’a), 132.3 (C-8a), 130.0
(C-4), 129.5 (C-2”,6”), 129.3 (C-7’), 129.2 (C-5), 129.1 (C-3”,5”), 128.7 (C-4a), 128.3 (C-3’),
128.2 (C-2’), 128.0 (C-4”), 127.9 (C-6’), 127.1 (C-7), 126.9 (C-4’), 126.7 (C-5’), 126.2 (C-8’),
123.0 (C-6), 122.0 (C-8), 120.1 (C-3), 116.8 (C-1), 70.7 (C-9), 59.7 (C-11), 40.3 (C-10). Anal.
calcd. for C29H25NO (403,51): C, 86.32; H, 6.24; N, 3.47. Found: C, 86.39; H, 6.19; N, 3.51.
24

ACCEPTED MANUSCRIPT
General procedure for the synthesis of naphth[1,2-e][1,3]oxazino[2,3-a]benz[c]azepine 3dA
and naphth[1,2-e][1,3]oxazino[2,3-a]thienopyridines (9cA and 9dA) starting from tertiary
aminonaphthols (13 and 14)
The mixture of the appropriate tertiary aminonaphthol (0.44 mmol) and 4,5-dihydro-3H-
benz[c]azepine (1, 58 mg, 0.4 mmol) or 6,7-dihydrothieno[3,2-c]pyridine (8, 48 mg, 0.4 mmol) in
1,4-dioxane (5 mL) was placed in a 10 mL reaction vial and heated in a CEM microwave reactor for
60 min at 80 °C. The solvent was then evaporated under reduced pressure and the desired products
were crystallized from methanol (6-8 mL) and then recrystallized from methanol (4-6 mL).
(7aS*,16R*)-16-Naphth-2-yl-naphth[1,2-e][1,3]oxazino[2,3-a]benz[c]azepine (3dA)
White powder. Rf = 0.85 (4:1, n-hexane:EtOAc). Mp: 194-198 °C. Yield: 109 mg (64%). 1H NMR
(DMSO-d6, 500 MHz):7.87 (d, J = 7.8 Hz, 1H, H-5’), 7.86 (d, J = 7.8 Hz, 1H, H-4’), 7.84 (d, J =
8.8 Hz, 1H, H-5), 7.82 (d, J = 2.5 Hz, 1H, H-1’), 7.67 (d, J = 8.0 Hz, 1H, H-8’), 7.62 (d, J = 7.8 Hz,
1H, H-3’), 7.45-7.42 (m, 2H, H-7’ and H-4), 7.38 (t, J = 7.8 Hz, 1H, H-6’), 7.30 (d, J =7.8 Hz, 1H,
H-1), 7.27 (t, J = 7.8 Hz, 1H, H-3), 7.24 (t, J = 7.8 Hz, 1H, H-2), 7.18 (d, J = 8.8 Hz, 1H, H-6), 7.16
(t, J = 7.8 Hz, 1H, H-9), 7.12 (d, J = 7.8 Hz, 1H, H-11), 6.98 (t, J = 7.8 Hz, 1H, H-10), 6.81 (d, J =
7.8 Hz, 1H, H-8), 5.73 (s, 1H, H-7a), 5.63 (s, 1H, H-16), 3.32-3.28 (m, 1H, H-14A), 3.24-3.21 (m,
H-14B), 3.02-2.98 (m, 1H, H-12A), 2.85-2.81 (m, 1H, H-12B), 1.94-1.92 (m, 1H, H-13A), 1.85-1.81
13
(m, 1H, H-13B); C NMR (DMSO-d6, 125 MHz): 153.8 (C-6a); 142.7 (C-7b), 141.7 (C-2’), 135.8
(C-11a), 133.0 (C-16b), 132.9 (two coalesced lines, C-4’a and C-8’a), 130.9 (C-8), 130.0 (C-11),
129.6 (C-5), 129.4 (C-4a), 129.3 (C-9), 129.1 (C-1’), 128.5 (C-4), 128.4 (two coalesced lines, C-5’
and C-8’), 128.2 (C-3’), 128.0 (C-4’), 127.1 (C-2), 126.7 (two coalesced lines, C-6’ and C-7’),
126.5 (C-10), 124.0 (C-3), 123.4 (C-1), 118.9 (C-6), 113.0 (C-16a), 91.0 (C-7a), 63.2 (C-16), 53.1
(C-14), 34.8 (C-12), 28.8 (C-13). Anal. calcd. for C31H25NO (427,54): C, 87.09; H, 5.89; N, 3.28.
Found: C, 87.02; H, 5.93; N, 3.31.
(7aS*,14R*)-14-Naphth-1-yl-naphth[1,2-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-
c]pyridine (9cA)
White powder. Rf = 0.75 (4:1, n-hexane:EtOAc). Mp: 144-147 °C. Yield: 104 mg (61%). 1H NMR
(DMSO-d6, 500 MHz): 8.58 (d, J = 8.1 Hz, 1H, H-8’), 7.99 (d, J = 8.1 Hz, 1H, H-5’), 7.89 (d, J =
25

ACCEPTED MANUSCRIPT
8.9 Hz, 1H, H-11), 7.87 (d, J = 8.9 Hz, 1H, H-12), 7.84 (d, J = 8.0 Hz, 1H, H-4’), 7.82 (d, J = 8.0
Hz, 1H, H-2’), 7.72 (dd, J = 8.2 Hz and 8.2 Hz, 1H, H-7’), 7.60 (dd, J = 8.2 Hz and 8.2 Hz, 1H, H-
6’), 7.32 (d, J = 5.2 Hz, 1H, H-2), 7.31-7.27 (m, 2H, H-10 and H-3’), 7.20 (d, J = 7.5 Hz, 1H, H-8),
7.16 (d, J = 8.9 Hz, 1H, H-13), 6.40 (s, 1H, H-7), 5.67 (s, H-14a), 3.69 (dd, J = 11.4 Hz and 5.0 Hz,
13
1H, H-5A), 3.24 (td, J = 11.4 Hz and 5.0 Hz, 1H, H-5B), 3.05-2.93 (m, 2H, H-4A and H-4B); C
NMR (DMSO-d6, 125 MHz): 152.1 (C-13a), 138.3 (C-3a), 138.2 (C-1’), 133.4 (C-4’a), 133.4 (C-
14b), 132.2 (C-7b), 131.6 (C-8’a), 129.7 (C-12), 129.6 (C-11), 129.2 (C-11a), 129.0 (C-5’), 128.7
(C-4’), 127.9 (C-2’), 127.1 (C-9), 127.0 (C-7’), 126.6 (C-1), 126.4 (C-6’), 125.2 (two coalesced
lines, C-10 and C-3’), 125.1 (C-8’), 124.3 (C-2), 123.0 (C-8), 118.8 (C-13), 111.3 (C-7a), 78.9 (C-
14a), 58.3 (C-7), 45.3 (C-5), 26.0 (C-4). Anal. calcd. for C28H21NOS (419,54): C, 80.16; H, 5.05; N,
3.34. Found: C, 80,24; H, 5,01; N, 3.31.
(7aS*,14R*)-14-Naphth-2-yl-naphth[1,2-e][1,3]oxazino[2,3-a]-6,7-dihydrothieno[3,2-
c]pyridine (9dA)
White powder. Rf = 0.85 (4:1, n-hexane:EtOAc). Mp: 240-242 °C. Yield: 106 mg (62%). 1H NMR
(DMSO-d6, 500 MHz, 55 oC): 7.87 (d, J = 8.6 Hz, 1H, H-4’), 7.86-7.82 (m, 3H, H-5’, H-11 and H-
12), 7.67 (d, J = 7.9 Hz, 1H, H-8’), 7.64 (dd, J = 8.6 Hz and 1.6 Hz, 1H, H-3’), 7.45 (br s, 1H, H-
1’), 7.45-7.42 (m, 3H, H-5’, H-7’ and H-8), 7.39 (t, J = 7.9 Hz, 1H, H-6’), 7.31-7.26 (m, 3H, H-3,
H-9 and H-10), 7.12 (d, J = 8.9 Hz, 1H, H-13), 7.00 (d, J = 5.1 Hz, 1H, H-1), 5.80 (s, 1H, H-7),
5.64 (s, 1H, H-14a), 3.37 (dd, J = 10.9 Hz and 5.5 Hz, 1H, H-5A), 3.22 (td, J = 10.9 Hz and 3.4 Hz,
1H, H-5B), 3.15-3.11 (m, 1H, H-4A), 2.93 (dd, J = 16.1 Hz and 3.0 Hz, 1H, H-4B); 13C NMR
o
(DMSO-d6, 125 MHz, 55 C): 151.9 (C-13a), 140.7 (C-2’), 138.2 (C-3a), 133.6 (C-14b), 132.9 (C-
4’a), 132.5 (C-7b), 129.6 (C-12), 129.2 (C-11a), 129.0 (C-11), 128.4 (C-4’), 128.3 (C-8’), 128.0
(two coalesced lines, C-1’ and C-3’), 127.8 (C-5’), 127.0 (C-9), 126.6 (C-1), 126.5 (two coalesced
lines, C-6’ and C-7’), 125.7 (C-8’a), 124.1 (two coalesced lines, C-2 and C-10), 123.0 (C-8), 118.9
(C-13), 111.4 (C-7a), 79.1 (C-14a), 61.7 (C-7), 46.0 (C-5), 26.0 (C-4). Anal. calcd. for C28H21NOS
(419,54): C, 80.16; H, 5.05; N, 3.34. Found: C, 80,24; H, 5,01; N, 3.31.
1-(Hydroxy(naphthalen-1-yl)methyl)naphthalen-2-ol (19b)
Yellow powder. Rf = 0.90 (2:1, n-hexane:EtOAc). Mp.: 134-136 °C. Due to extremely overlapped
aromatic signals with poor resolution, only the unambiguous assignments of H-9 C-3 and C-9 of
diagnostic importance are given along with 1H chemical shift ranges and the signals of naphthalene
1
CH carbons detected by 2D-HMQC measurements: H NMR (DMSO-d6, 500 MHz): 7.98 (d, J =
8.0 Hz, 1H), 7.9-7.7 (m, 6H), 7.61 (t, J = 8.0 Hz, 1H), 7.46 (t, J=7.8 Hz 1H), 7.4-7.1 (m, 5H), 6.50
26

ACCEPTED MANUSCRIPT
(s, 1H, H-9); 13C NMR (DMSO-d6, 125 MHz): 129.9, 129.7, 129.3 (two signals as detected by two
HMQC cross peaks), 129.2, 128.1, 127.6, 127.3, 126.9, 126.4, 126.3, 122.9, 121.9, 120.2 (C-3),
63.8 (C-9).
General procedure for the synthesis of various substituted tertiary aminonaphthols (20-22,
24-25)
The appropriate amine (0.4 mmol) and aldehyde (0.4 mmol) component were placed in a 10 mL
reaction vial and heated in an oil bath at 70 °C for 1 h. Then 2-naphthol was added and stirred under
neat conditions at 70 °C. After 7 hours reaction time, the desired products were crystallized from
methanol (4-6 mL) and then recrystallized from methanol (6-8 mL).
1-(Naphthalen-1-yl(pyrrolidin-1-yl)methyl)naphthalen-2-ol (20)
1
Yellow powder. Rf = 0.80 (2:1, n-hexane:EtOAc). Yield: 114 mg (81%). Mp.: 109-112 °C. H
NMR (DMSO-d6, 500 MHz): 8.91 (d, J = 8.2 Hz, 1H, H-8’), 7.95 (d, J = 8.2 Hz, 1H, H-5’), 7.82 (d,
J = 8.0 Hz, 1H, H-4’), 7.73-69 (m, 4H, H-4, H-5, H-2’ and H-7’), 7.64 (d, J = 7.8 Hz, 1H, H-8),
7.57 (dd, J = 8.2 Hz and 7.6 Hz, 1H, H-6’), 7.40 (t, J = 8.0 Hz, 1H, H-3’), 7.18-7.11 (m, 3H, H-3,
13
H-6 and H-7), 6.37 (s, 1H, H-9), 2.6 (very br s, 4H, H-2”,5”), 1.74 (br s, 4H, H-3”,4”) C NMR
(DMSO-d6, 125 MHz): 156.7 (C-2), 137.7 (C-1’), 133.9 (C-4’a), 132.4 (C-8a), 131.9 (C-8’a), 129.6
(two coalesced lines, C-5 and C-5’), 129.0 (C-4), 128.9 (C-4’), 128.5 (C-4a), 127.3 (C-7’), 126.9
(C-2’), 126.8 (C-7), 126.3 (C-3’), 126.2 (C-6’), 123.9 (C-8’), 122.7 (C-6), 121.8 (C-8), 120.3 (C-3),
117.8 (C-1), 62.6 (C-9), 53.7 (C-2”,5”), 23.4 (C-3”,4”). Anal. calcd. for C25H23NO (353.46): C,
84.95; H, 6.56; N, 3.96. Found: C, 84.88; H, 6.64; N, 3.90.
1-(Naphthalen-1-yl(piperidin-1-yl)methyl)naphthalen-2-ol (21)
1
Orange powder. Rf = 0.85 (2:1, n-hexane:EtOAc). Mp.: 187-189 °C. Yield: 113 mg (77%). H
NMR (DMSO-d6, 500 MHz): 8.86 (d, J = 8.2 Hz, 1H, H-8’), 7.98 (d, J = 8.2 Hz, 1H, H-5’), 7.85 (d,
J = 8.0 Hz, 1H, H-4’), 7.77 (dd, J = 8.2 Hz and 7.6 Hz, 1H, H-7’), 7.74 (d, J = 8.9 Hz, 1H, H-8),
7.71 (dd, J = 7.5 Hz and 2.1 Hz, 1H, H-5), 7.63 (d, J = 8.0 Hz, 1H, H-2’), 7.61 (dd, J = 8.2 Hz and
7.6 Hz, 1H, H-6’), 7.56 (d, J = 7.9 Hz, 1H, H-8), 7.41 (t, J = 8.0 Hz, 1H, H-3’), 7.18-7.11 (m, 3H,
H-3, H-6 and H-7), 6.29 (s, 1H, H-9), 2.28 and 2.18 (2xbr s, 2x2H, H-2”,6”), 1.55 (br s, 4H, H-
3”,5”), 1.28 (br s, 2H, H-4) 13C NMR (DMSO-d6, 125 MHz): 152.9 (C-2), 135.8 (C-1’), 133.8 (C-
4’a), 132.9 (C-8a), 132.6 (C-8’a), 129.6 (C-5’), 129.5 (C-4), 129.1 (C-5), 129.0 (C-4’), 128.6 (C-
4a), 127.5 (C-7’), 127.3 (C-2’), 126.9 (C-7), 126.4 (C-3’), 126.3 (C-6’), 123.8 (C-8’), 122.7 (C-6),
27

ACCEPTED MANUSCRIPT
121.6 (C-8), 120.4 (C-3), 117.1 (C-1), 64.2 (C-9), 50.1 (C-2”,6”), 26.5 (C-3”,5”), 25.0 (C-4”). Anal.
calcd. for C26H25NO (367,48): C, 84.98; H, 6.86; N, 3.81. Found: C, 85.07; H, 6.93; N, 3.69.
1-((methyl(phenethyl)amino)(naphthalen-1-yl)methyl)naphthalen-2-ol (22)
Yellow powder. Rf = 0.90 (4:1, n-hexane:EtOAc). Mp.: 71-73 °C. Yield: 133 mg (80%). 1H NMR
o
(DMSO-d6, 500 MHz, 55 C): 8.34 (d, J = 8.2 Hz, 1H, H-8’), 7.97 (d, J = 8.2 Hz, 1H, H-5’), 7.84
(d, J = 8.0 Hz, 1H, H-4’), 7.76 (dd, J = 8.2 Hz and 7.6 Hz, 1H, H-7’), 7.73 (d, J = 7.9 Hz, 1H, H-5),
7.71 (d, J = 8.6 Hz, 1H, H-4), 7.68 (d, J = 7.8 Hz, 1H, H-8), 7.66 (d, J = 8.0 Hz, 1H, H-2’), 7.57
(dd, J = 8.2 Hz and 7.6 Hz, 1H, H-6’), 7.39 (t, J = 8.0 Hz, 1H, H-3’), 7.20 (tt, J = 7.8 Hz and 2.0
Hz, 1H, H-4”), 7.16-7.11 (m, 5H, H-3, H-6, H-7 and H-3”,5”), 6.96 (d, J = 7.9 Hz, 2H, H-2”,6”),
6.38 (s, 1H, H-9), 2.8 (very br s, 7H, H-10, H-11and H-12);13C NMR (DMSO-d6, 125 MHz, 55 oC):
156.7 (C-2), 136.7 (C-1’), 133.9 (C-4’a), 132.9 (C-8a), 132.6 (C-8’a), 129.6 (two coalesced lines,C-
5 and C-5’), 129.0 (two coalesced lines, C-4’ and C-7’), 128.8 (two coalesced lines, C-2”,6” and C-
3”,5”), 128.6 (C4a), 127.4 (two coalesced lines, C-4 and C-2’), 126.7 (C.4”), 126.5 (C-7), 126.2
(two coalesced lines, C-3’ and C-6’), 123.8 (C-8’), 122.6 (C-6), 121.9 (C-8), 120.3 (C-3), 117.5 (C-
1), 64.6 (C-9), 56.8 (C-11), 33.8 (C-10), 27.6 (C-12). Anal. calcd. for C30H27NO (417,54): C, 86.30;
H, 6.52; N, 3.35. Found: C, 86.39; H, 6.48; N, 3.41.
1-((Benzyl(methyl)amino)(4-methoxyphenyl)methyl)naphthalen-2-ol (24)
1
Pale pink powder. Rf = 0.80 (2:1, n-hexane:EtOAc). Mp.: 110-112 °C. Yield: 123 mg (80%). H
NMR (DMSO-d6, 500 MHz): 8.09 (d, J = 7.9 Hz, 1H, H-8), 7.77 (d, J = 7.9 Hz, 1H, H-5), 7.74 (d,
J = 8.9 Hz, 1H, H-4), 7.62 (d, J = 8.6 Hz, 2H, H-2’,6’), 7.43 (t, J = 7.8 Hz, 1H, H-7), 7.38 (t, J = 7.8
Hz, 2H, H-3”,5”), 7.32-7.28 (m, 3H, H-2”,6” and H-4”), 7.26 (t, J = 7.9 Hz, 1H, H-6), 7.14 (d, J =
13
8.9 Hz, 1H, H-3), 6.87 (d, J = 8.6 Hz, 2H, H-3’,5’), 5.44 (s, 1 C NMR (DMSO-d6, 125 MHz):
159.2 (C-4’), 155.1 (C-2), 137.7 (C-1”), 132.8 (C-1’), 132.3 (C-8a), 130.2 (C-2’,6’), 129.6 (C-4),
129.5 (C-2”,6”), 129.2 (C-3”,5”), 129.1 (C-5), 128.7 (C-4a), 128.0 (C-4”), 127.0 (C-7), 122.9 (C-6),
122.0 (C-8), 120.0 (C-3), 117.4 (C-1), 114.6 (C-3’,5’), 69.9 (C-9), 59.5 (C-11), 55.5 (OCH3), 39.8
(C-10). Anal. calcd. for C27H28N2O (396,52): C, 81.78; H, 7.12; N, 7.06. Found: C, 81.88; H, 7.11;
N, 6.99.
1-((Benzyl(methyl)amino)(4-nitrophenyl)methyl)naphthalen-2-ol (25)
1
Light orange powder. Rf = 0.85 (2:1, n-hexane:EtOAc). Mp.: 81-83 °C. Yield: 132 mg (83%). H
NMR (DMSO-d6, 500 MHz): 8.26 (d, J = 7.8 Hz, 1H, H-8), 8.15 (d, J = 8.9 Hz, 2H, H-3’,5’), 7.98
(d, J = 8.9 Hz, 2H, H-2’,6’), 7.76 (d, J = 7.9 Hz, 1H, H-5), 7.73 (d, J = 8.9 Hz, 1H, H-4), 7.44 (dd, J
= 8.4 Hz and 7.0 Hz, 1H, H-7), 7.36 (t, J = 7.8 Hz, 2H, H-3”,5”), 7.31 (d, J = 7.3 Hz, 2H, H-2”,6”),
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ACCEPTED MANUSCRIPT
7.28 (t, J = 7.3 Hz, 1H, H-4”), 7.25 (t, J = 7.7 Hz, 1H, H-6), 7.15 (d, J = 8.9 Hz, 1H, H-3), 5.72 (s, 1
13C NMR (DMSO-d6, 125 MHz): 155.0 (C-2), 149.0 (C-1’), 147.3 (C-4’), 137.6 (C-1”), 132.3 (C-
8a), 130.4 (C-4), 129.9 (C-2’,6’), 129.4 (C-2”,6”), 129.2 (C-5), 129.1 (C-3”,5”), 128.8 (C-4a), 128.0
(C-4”), 119.9 (C-3), 116.6 (C-1), 68.9 (C-9), 59.7 (C-11), 40.5 (C-10). Anal. calcd. for C25H22N2O3
(398,45): C, 75.36; H, 5.57; N, 7.03. Found: C, 75.42; H, 5.59; N, 6.98.
Acknowledgements
The authors thank the Hungarian Research Foundation (OTKA No. K115731) and the Ministry of
National Economy, National Research Development and Innovation Office (GINOP-2.3.2-15-2016-
00038) for financial support.
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