1H, 13C and 15N NMR of spiro acridines integrated with pyrrole scaffolds

Full text of DOI:10.1002/mrc.4974

Mária Vilková (Orcid ID: 0000-0003-2833-7361)
Michal Šoral (Orcid ID: 0000-0002-4537-7173)
Ivan Potočňák (Orcid ID: 0000-0001-6923-8816)
Danica Sabolová (Orcid ID: 0000-0003-0942-0039)
1H, 13C and 15N NMR of spiro acridines integrated with pyrrole scaffolds
Mária Vilková1, Michal Šoral2, Michal Bečka1, Ivan Potočňák1, Danica Sabolová1,
Tibor Béres3, Michal Dušek4, Ján Imrich1
ORCID
Mária Vilková
Michal Šoral
Michal Bečka
Ivan Potočňák
Danica Sabolová
Tibor Béres
0000-0003-2833-7361
0000-0002-4537-7173
0000-0001-6923-8816
0000-0003-0942-0039
Michal Dušek
Ján Imrich
1Institute of Chemistry, Faculty of Science, P. J. Šafárik University, Moyzesova 11, 040 01
Košice, Slovak Republic
2Central Laboratories, Faculty of Chemical and Food Technology, Slovak University of
Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic
3Centre of the Region Haná for Biotechnological and Agricultural Research, Department of the
Phytochemistry, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71 Olomouc, Czech
Republic
4Institute of Physics of the Czech Academy of Sciences, Na Slovance 2, 182 21 Praha 8, Czech
Republic
Correspondence
Mária Vilková, Institute of Chemistry, Faculty of Science, P. J. Šafárik University, Moyzesova
11, 040 01 Košice, Slovak Republic.
Email: maria.vilkova@upjs.sk
1
INTRODUCTION
Acridines are important organic compounds with potent biological properties [1–3] which
are in focus of our long-term research. The hydrazide-hydrazone fragment CH=N-NH-CO
represents a significant structural unit with a wide range of biological activities such as
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antitumor,[4,5] antimicrobial,[6] anti-inflammatory,[7] and antituberculotic.[8] The use of
acridine derivatives in the synthesis of hydrazide-hydrazones has seemed favourable to us
because of their interesting antiviral,[9] antibacterial[10] and antitumor properties.[11] In
connection with our ongoing studies on the new acridine derivatives, we decided to prepare
compounds containing both hydrazide-hydrazone and acridine substructures for utilization in
the synthesis of heterocycles. Originally, we intended to obtain novel compounds 3 (Scheme 1)
from starting N'-[(E)-acridin-9-ylmethylidene]-2-cyanoacetohydrazide (2a). We have found,
however, that 2a rapidly reacted with another molecule of acridin-9-carbaldehyde (1a) via
methylene carbon forming a non-isolated intermediate 4a and eventually a spiro compound 5a
due to spontaneous spirocyclization. As it was previously reported,[12–14] we again observed
a particular susceptibility of acridine C-9 carbon to the nucleophilic attack enabling subsequent
formation of a five-membered spiro ring. Owing to a rapid reaction of the hydrazide 2a with
aldehyde 1a, further derivatization of 2a was not possible. Inspired by this reaction course, we
changed the strategy and attempted a reaction of substituted benzaldehydes 1b–i with 2-
cyanoacetohydrazide affording acylhydrazones 2b–i. Their subsequent reaction with the
aldehyde 1a provided non-isolable intermediates 4b–i which again rapidly spirocyclized to 1-
[(E)-(phenylmethylidene)amino]-5-oxo-1,5-dihydro-10'H-spiro[acridine-9',2-pyrrole]-4-
carbonitriles 5b–i (Scheme 2). In our work we synthesized altogether nine derivatives of 5, of
which five derivatives, 5b,d,e,g,i, have been described previously.[15–17] Although 1H and 13C
NMR data for the compounds 5b,d,e,g,i were already published in papers [15–17], reporting
also their biological activity, the data were often improperly referenced and multiplicities of the
acridine and aromatic proton signals were unduly reported as simple multiplets with lacking or
incorrect coupling constants.[15–17] In addition, in the reference [15], there were some missing
13C signals, typographical errors, and insufficient data for discussion about configuration of the
linker double bond. In the reference [16], description of p-disubstituted rings proton signals and
19F-13C couplings were problematic. Therefore, we extensively applied 1D and 2D NMR
techniques to exactly confirm the structure of the target compounds by complete and precise
1H, 13C and 15N resonance assignments. For that purpose, we also used the X-ray
crystallography.
2
RESULTS AND DISCUSSION
The complete structural characterization of synthesized compounds was achieved by the
1
1
combined use of 1D and 2D NMR techniques, such as H,13C-HSQC, H,13C-HMBC and
1H,15N-HMBC. Although the derivatives 2b–i are known (Scheme 2), their 15N NMR chemical
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1
shifts and coupling constants JC7/H7 had not been previously published. Now we present the
structural data for the both isomers of 2b–i in Tables S2–S8 (see Supplementary Information
(SI)). The geometric configuration of N6=C7 double bond was resolved on the basis of
heteronuclear coupling constants (1JC7/H7 = 162.6–171.6 Hz, Table S8) [18] which indicated its
E configuration in isomers 2a–i, as we previously reported.[19] The pairs of isomers of 2a–i
differ in configuration of the amide C4N5 bond (Figure 1).
The 1H, 13C and 15N NMR chemical shifts for derivatives 5a–i are collected in Tables 2–4.
The procedures used to assign NMR data of the compound 5a (Scheme 1) are explained in
1
detail here. The H NMR spectrum suggested the presence of two acridine rings and another
three types of protons with singlet shaped signals. Analysis of the COSY spectrum (Figure S37,
see SI) allowed resolution of the protons of two acridine rings. The signals of the protons and
carbons 1'–8' as well as 1''–8'' were easily assigned using homonuclear COSY correlations,
heteronuclear one-bond 1H,13C-HSQC correlations, and three-bond 1H,13C-HMBC
1
correlations. The H,13C-HMBC spectra (Figure 2) allowed to assign quaternary carbons C-
8'a,9'a/C-4'a,10'a and C-8''a,9''a/C-4''a,10''a. Similarly, as reported previously,[14] deshielding
of C-4''a,10''a carbons to 148.1 ppm and C-8''a,9''a ones to 122.8 ppm indicated an aromatic
acridin-9-yl moiety and shielding of C-4'a,10'a ones to 138.6 ppm and C-8'a,9'a ones to 111.0
1
ppm indicated a 9,10-dihydroacridin-9-ylidene structure. The H,13C-HMBC signals allowed
assignment of the other quaternary carbons (Figure 3). The signal of H-7 hydrogen was resolved
by HMBC correlations (Figure 4) with the carbons C-8''a,9''a from the H-3 one, which had a
three bond correlation with quaternary carbons C-8'a,9'a and two bond correlation with spiro
carbon C-9' (C = 68.8 ppm) of the 9,10-dihydroacridin-9-ylidene moiety. Moreover, the proton
H-3 exhibited correlations with quaternary carbons at 108.6 ppm and 161.1 ppm, which
unequivocally pertained to C-4 and C-5 carbons, respectively. The singlet at H = 9.93 ppm
with no 1H,13C-HSQC correlation should correspond to a H-10' proton.
1
The H,15N-HMBC spectra were used as a final and unequivocal tool for specific
assignments (Figure 5). Strong correlations between H-7 (H = 9.31 ppm) and N-1 (N = -174.2
ppm) and between H-3 (H = 8.73 ppm) and N-1 (N = -174.2 ppm) were observed in these
spectra, whereas the cross peak between H-7 (H = 9.31 ppm) and N-6 (N = -52.9 ppm) was
weak. Geometric configuration of the N6=C7 double bond in 5a,b,e was resolved by a
1
heteronuclear coupling constant JH7/C7 with values 166.2 Hz for 5b (Figure S48 in SI), 165.6
Hz for 5c (Figure S52 in SI), and 168.6 Hz for 5e and 5f, (Figures S60 and S64 in SI), and by
a value of 2JH7/N6  0 Hz (see 1H,15N-HMBC spectra in SI)[18], which all indicated the N6=C7
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double bond to be in the E configuration (Figure 6). Similarity of chemical shifts of 5a–i as
well as determined X-ray structure of 5f (Figure 7) allowed to describe 5a–i derivatives as the
E isomers.[19]
Comparison of 1H and 13C chemical shifts of 5b,g with already published data
The published NMR spectral data for derivatives 5b,g in ref. 15 contain partly an incorrect
information. Their assignments, which were reported using a different numbering system of
their skeleton, are listed alongside ours in Table 5. In contrast to our assignments, Almeida and
1
co-workers [15–17] did not mention any H and 13C chemical shift reference compounds
resulting in shifts of all chemical shifts in comparison to our reported data, which are referenced
in accordance with ref. [20].
The procedure for assignment of the proton and carbon resonances of 5b and 5g is similar
to the aforementioned discussion for derivative 5a. Thus, we describe only the discrepancies in
1H and 13C chemical shift assignment in 5b and 5g derivatives. Incorrect assignments were
found for carbons C-4, C-8, C-1',8', C-4',5', C-3'',5'', C-4'' and protons H-1',8' and H-4',5' in the
derivative 5b and C-4, C-5, C-8, C-1',8', C-4',5', C-1'', C-2'',6'', C-3'',5'', C-4'' and protons H-
4',5', H-2'',6'' and H-3'',5'' in the derivative 5g. First, the authors swapped the resonances of
carbon atoms C-4 and C-8 in both derivatives, AMTAC-01 and AMTAC-02 (our 5b and 5g,
respectively). Their assignment relied on the observation of HMBC correlations between the
proton H-3 and above-mentioned carbon atoms, as they presented in Figure 2B for the
derivative AMTAC-01 (our 5b). While inspecting their 1H,13C-HMBC spectra (in SI of the ref.
[15]), the correlation of carbon C-8 with proton H-3 was indeed found, but it was missing for
the carbon C-4 separated by two bonds. We observed the same correlations (Table 6, Figure
S47 in SI).
The correct assignment can be easily deduced from a generally very limited range of
resonance frequencies of cyano groups in organic molecules, including acylhydrazones 2a–i
(see SI), where the cyano carbon signal can be unambiguously assigned. Despite differences of
the neighborhood of cyano groups in the derivatives 2 and 5, their chemical shifts remain almost
unchanged. It is expected that the carbon chemical shift of carbon C-4 is decreased due to
additional shielding from the sp-molecular orbital of the cyano triple bond, thus being observed
at C = 108.6 ppm.
Second, the authors interchanged in 5b the resonances of H-1',8' and H-4',5' as well as these
of the attached carbons.[15] They based their assignment on the use of HMBC correlations,
4
specifically a declared mock JCH correlation between the acridine NH-10' proton and C-1',8'.
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But, such a 4JCH coupling is doubtful, practically 0 Hz, and it can be easily proven that in reality
the observed were the 3JCH correlations of NH-10' proton with C-4',5'. If the former was true,
then the proton directly bonded to carbon with the chemical shift C = 115.44 ppm should have
to correlate with the spiro carbon through a strong 3JCH correlation. As this is not true, according
to their HMBC spectrum, thus the two proton-carbon pairs at the end of the dihydroacridine
spin systems are erroneously swapped. The correctness of our assignment is supported by the
observation of a 3JNH correlation between the protons H-4',5' (H = 7.02 ppm, C = 115.1 ppm)
and the nitrogen N-10' (N = -283.9 ppm). Surprisingly, two other protons of acridine ring were
correctly assigned.[15] The situation is more complicated in the case of AMTAC-02 (our 5g).
The two spin systems (acridine and p-substituted phenyl ring) can be easily distinguished by
the COSY spectrum (even from the spectrum supplied by the authors in ref. [15]). The two
types of protons of the p-disubstituted phenyl ring (H = 6.89 and 7.32 ppm) only correlate with
1
each other whilst the remaining protons in the aromatic part of the H spectrum form a mutual
correlation network, thus belonging to the acridine core. However, the authors wrongly
assigned the signal H = 6.89 ppm to the protons H-4',5' of the acridine core and that H = 6.99
ppm to the p-disubstituted phenyl ring. Using HSQC correlation spectra, this incorrect proton
assignments were spread on the 13C domain.
Third, they interchanged resonances of aromatic phenyl carbons C-3'',5'' and C-4'' in the
derivative AMTAC-01 (our 5b). The resonances of carbons C-1'' and C-2'',6'' we
unambiguously assigned by observing HMBC correlations between the proton H-7 and carbons
C-1'' and C-2'',6'' (Table 6). Though it was impossible to determine COSY correlations between
the phenyl protons because of the large overlap, we could use the HSQC spectrum to resolve
the carbons C-3'',5'' and C-4'', because the C-3'',5'' resonance (both the HSQC correlation peak
and the 13C signal) has an approximately double integral intensity than the C-4'' resonance. Thus
the identities of phenyl protons H-3'',5'' and H-4'' were confirmed. Furthermore, HMBC showed
3
expected JCH correlations between protons H-3'',5'' and carbon C-1'' and between protons H-
2'',6'' and carbon C-4'' (Table 6). Fourth, their C-5 and C-4'' assignments are the opposite to
ours. Our assignment were based upon the HMBC correlations between protons of methoxy
group (H = 3.73 ppm) with carbon C-4'' (C = 161.2 ppm) and proton H-3 (H = 8.52 ppm) with
carbon C-5 (C = 160.4 ppm, Table 5). Finally, Almeida et al. [15] declared in the compound
name that they obtained the E-isomer of the compound, but this claim was not discussed or
proved within the article. In a recent article our group has shown that the E-configuration is not
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always favored in derivatized acridine hydrazones and we have demonstrated the use of
methods that enable determination of the correct configuration.[19]
3
Experimental
Compounds 5a–i were prepared by reacting the appropriate cyanoacetohydrazide 2 and
acridin-9-carbaldehyde (1a, see SI). Analytical TLC was performed on pre-coated aluminium
sheets of silica gel 60 F254 (Merck, Germany) and the compounds were visualized in the UV
light. The melting points were recorded on a Boetius apparatus and are uncorrected.
Nuclear magnetic resonance data were collected on a Varian VNMRS 600 spectrometer
1
operating at 599.87 MHz for H, 150.84 MHz for 13C, and 60.79 MHz for 15N. The
concentration of all samples was approximately 10 mg/0.6 mL of DMSO-d6, and the chemical
shifts were referenced to the residual solvent peak (1H NMR 2.50 ppm and 13C NMR 39.5 ppm).
The NMR data were recorded at 300 K, with chemical shifts  reported in parts per million and
15
coupling constants J in Hertz. The N chemical shifts were obtained from two dimensional
1H,15N-HMBC experiments with gradient coherence selection, performed using a standard
15
pulse sequence from the Varian pulse library. For the N chemical shifts, CH3NO2 was used
as an external reference (0.0 ppm). The 2D experiments gCOSY, zTOCSY, NOESY, gHSQC
and gHMBC were run using the standard Varian software. All data were analysed using MNova
7.1.1 (2012) software. The spectral acquisition parameters are collected in Table S1 (see SI).
4
CONCLUSIONS
In this study, five novel derivatives, N'-[(E)-acridin-9-ylmethylidene]-2-
cyanoacetohydrazide (2a), 1-[(E)-(acridin-9-ylmethylidene)amino]-5-oxo-1,5-dihydro-10'H-
spiro[acridine-9',2-pyrrole]-4-carbonitrile (5a) and 1-[(E)-(acridin-9-ylmethylidene)amino]-5-
oxo-1,5-dihydro-10'H-spiro[acridine-9',2-pyrrole]-4-carbonitriles 5c,f,h have been synthesized
13
15
and characterized by 1H NMR, C NMR, N NMR and HR-MS spectroscopy, as well as by
the single crystal X-ray crystallography of the compound 5f.
SUPPORTING INFORMATION
Crystallographic data for the structure 5f had been deposited with the Cambridge
Crystallographic Data Centre as CCDC 1882996.
The
raw
NMR
data
were
uploaded
in
an
open
repository:
http://uschovna.zoznam.sk/D1342688969406-KUdZkCstAXvxFFIHecxk.
This article is protected by copyright. All rights reserved.

ACKNOWLEDGEMENTS
This work was supported by the Grant Agency for Science of the Slovak Ministry of Education
(VEGA), grant. nos. 1/0016/18 and 1/0148/19. The crystallographic measurements used
instruments of the ASTRA lab established within the Operation Program Prague
Competitiveness - project CZ.2.16/3.1.00/24510. The authors gratefully acknowledge the
Research Centre for Industrial Synthesis of Drugs, ITMS 26240220061, supported by the
Research & Development Operational Program funded by the ERDF. We would like to thank
Prof. emeritus Jean-François Gal (University Cote d'Azur) for fruitful discussions regarding
mass spectrometry.
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[14] M. Vilková, M. Prokaiová, J. Imrich, Tetrahedron 2014, 70, 944.
[15] S. M. V. de Almeida, E. A. Lafayette, W. L. Silva, V. L. Serafim, T. M. Menezes, J. L.
Neves, A. L. T. G. Ruiz, J. E. de Carvalho, R. O. de Moura, E. I. C. Beltrão, L. B. C. Júnior,
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R
O
H
H
O
5
5
NH
3
3
RCHO
1b
NH
H2
N
CN
7
7
i
H
NH
N
CN
X
N
CN
1
EtOH
rt
EtOH
rt
1
N
N
O
N
O
3
1a
2a
1a EtOH
rt
8
NC
H
1''
O
NH
O
4
5
6
N
N
N
1
N
N
3
7
8'
9'
1'
N
8'a
9'a
4'a
10'a
N
H
5'
4'
5a
N
4a
a: R = Acr; b: R = Ph; c: R = 4-Me-Ph; d: R = 4-F-Ph; e: R = 4-Cl-Ph; f: R = 4-Br-Ph; g: 4-MeO-Ph; h: R = 2,6-diCl-Ph; i: 4-NO2-Ph
SCHEME 1
Synthesis of 1-[(E)-(acridin-9''-ylmethylidene)amino]-5-oxo-1,5-dihydro-10'H-spiro[acridine-
9',2-pyrrole]-4-carbonitrile (5a).
O
H
O
H2
N
CN
5
NH
3
NH
1a
7
R
N
CN1
EtOH
rt
EtOH
rt
R
R
H
O
1b-i
2b-i
H
8
NC
O
NH
O
N
N
4
5
6
N
1
N
1''
3
7
R
9'
8'
5'
1'
4'
8'a
10'a
9'a
4'a
N
H
N
4b-i
5b-i
a: R = Acr; b: R = Ph; c: R = 4-Me-Ph; d: R = 4-F-Ph; e: R = 4-Cl-Ph;
f: R = 4-Br-Ph; g: 4-MeO-Ph; h: R = 2,6-diCl-Ph; i: 4-NO2-Ph
SCHEME 2
Synthesis
of
substituted
1-[(E)-[(phenylmethylidene)amino]-5-oxo-1,5-dihydro-10'H-
spiro[acridine-9',2-pyrrole]-4-carbonitriles 5b–i.
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TABLE 1
Melting point Yield Yield
Color
Molecular
formula
HR-MS: m/z [M+H]+
[°C]
[mg]
[%]
calcd.
found
1-[(E)-(Acridin-9-ylmethylidene)amino]-5-oxo-1,5-dihydro-10'H-
260–261
38
28
yellow solid
yellow solid
yellow solid
yellow solid
C31H20N5O
478.1668
478.1665
5a
5b
5c
5d
5e
5f
spiro[acridine-9',2-pyrrole]-4-carbonitrile
5-Oxo 1-[(E)-(phenylmethylidene)amino]-1,5-dihydro-10'H-
spiro[acridine-9',2-pyrrole]-4-carbonitrile
234–235
231–232
233–234
247–248
245–246
236–237
257–258
153–154
51
62
53
66
83
83
92
72
56
66
56
67
76
85
86
71
C24H17N4O
C25H19N4O
C24H16FN4O
377.1402
391.1559
395.1308
411.1013
455.0507
407.1508
377.1405
391.1561
395.1308
411.1011
455.0508
407.1509
445.0622
421.1175a
1-[(E)-[(4''-Methylphenyl)methylidene]amino]-5-oxo-1,5-dihydro-
10'H-spiro[acridine-9',2-pyrrole]-4-carbonitrile
1-[(E)-[(4''-Fluorophenyl)methylidene]amino]-5-oxo-1,5-dihydro-
10'H-spiro[acridine-9',2-pyrrole]-4-carbonitrile
1-[(E)-[(4''-Chlorophenyl)methylidene]amino]-5-oxo-1,5-dihydro-
10'H-spiro[acridine-9',2-pyrrole]-4-carbonitrile
yellow solid C24H16ClN4O
yellow solid C24H16BrN4O
1-[(E)-[(4''-Bromophenyl)methylidene]amino]-5-oxo-1,5-dihydro-
10'H-spiro[acridine-9',2-pyrrole]-4-carbonitrile
1-[(E)-[(4''-Methoxyphenyl)methylidene]amino]-5-oxo-1,5-dihydro-
10'H-spiro[acridine-9',2-pyrrole]-4-carbonitrile
yellow solid
C25H18N4O2
5g
5h
5i
1-[(E)-[(2'',6''-Dichlorophenyl)methylidene]amino]-5-oxo-1,5-dihydro-
10'H-spiro[acridine-9',2-pyrrole]-4-carbonitrile
yellow solid C24H15Cl2N4O 445.0623
1-[(E)-[(4''-Nitrophenyl)methylidene]amino]-5-oxo-1,5-dihydro-10'H-
spiro[acridine-9',2-pyrrole]-4-carbonitrile
light brown
solid
C24H15N5O3
421.1175a
a
HR-MS: m/z [M]-
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TABLE 2
1H NMR chemical shifts (, ppm, DMSO-d6) for derivatives 5a–i.
5ae
5b
5cf
5d
5e
5f
5gg
5h
5i
No H
δH (mult, J, Hz)
8.55 (s)
8.73 (s)
9.31 (s)
8.55 (s)
8.53 (s)
8.55 (s)
8.55 (s)
8.41 (s)
8.52 (s)
8.59 (s)
8.60 (s)
3
7
8.40 (s)
8.35 (s)
8.49 (s)
8.44 (s)
8.42 (s)
8.33 (s)
8.47 (s)
7.00 (dd,
8.2, 1.4)
6.84 (ddd,
6.99 (dd,
8.0, 1.4)
6.83 (ddd,
7.00 (dd,
8.1, 1.4)
6.84 (ddd,
6.98 (dd,
8.2, 1.0)
6.84 (ddd,
7.04 (dd,
8.4, 1.2)
6.86 (ddd,
7.02 (dd,
8.2, 1.3)
6.84 (ddd,
7.24 (d, 8.2)
7.00 (d, 8.2) 7.00 (d, 8.0)
1',8'
2',7'
3',6'
6.94 (ddd,
6.84 (ddd, 6.84 (ddd,
8.2, 6.9, 1.4) 8.2, 7.2, 1.4) 8.0, 7.2, 1.2) 8.1, 7.2, 1.2) 8.2, 7.1, 1.2) 8.0, 7.1, 1.2) 8.2, 7.1, 1.0) 8.4, 6.6, 1.2) 8.2, 7.1, 1.3)
7.36 (ddd,
7.28 (ddd,
7.28 (ddd,
7.28 (ddd,
7.28 (ddd,
7.27 (ddd,
7.27 (ddd,
7.29 (ddd,
7.27 (mb)
8.2, 6.9, 1.4) 8.2, 7.2, 1.4)
8.3, 7.2, 1.4) 8.2, 7.1, 1.2) 8.0, 7.1, 1.1) 8.4, 7.1, 1.3) 8.4, 6.6, 1.2) 8.4, 7.1, 1.3)
7.02 (dd,
7.07 (d, 8.2)
7.02 (dd,
8.0, 1.4)
9.81 (s)
7.02 (dd,
8.3, 1.2)
9.81 (s)
7.01 (dd,
8.1, 1.3)
9.79 (s)
6.97 (dd,
8.4, 1.2)
9.78 (s)
7.04 (dd,
8.3, 1.3)
9.87 (s)
7.02 (d, 8.2) 7.02 (d, 8.0)
4',5'
10'
8.2, 1.4)
9.93 (s)
9.83 (s)
9.82 (s)
9.82 (s)
7.43 (dd,
8.8, 5.6)
7.35 (ma)
7.27 (mb)
7.39 (mc)
7.31 (d, 8.5) 7.32 (d, 8.9)
7.62 (d, 8.9)
2'',6''


7.35 (ma)
7.35 (ma)
7.14 (d, 8.0) 7.18 (t, 8.8)
7.39 (mc)
7.53 (d, 8.5) 6.89 (d, 8.9) 7.39 (md)
7.33 (md)
8.17 (d, 8.9)
3'',5''
4''








aoverlapped; boverlapped; coverlapped; dpartly overlapped; e7.77 (d, J 8.5, H-1'',8''), 7.49 (ddd, J 8.5, 6.6, 1.0, H-2'',7''), 7.81 (ddd, J 8.5, 6.6, 1.3, H-3'',6''), 8.12 (d, J 8.5, H-4'',5''); f2.25 (s, CH3);
g3.73 (s, OCH3).
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TABLE 3
13C NMR chemical shifts (, ppm, DMSO-d6) for derivatives 5a–i.
5aa
5b
5cb
5d
5e
5f
5gc
5h
5i
No C
δC (mult, J, Hz)
161.1 160.8 160.8
108.6 108.2 108.1
161.0 160.6 160.6
143.0 147.6 147.9
112.2 112.3 112.4
127.4 127.0 127.0
120.7 120.4 120.4
130.5 130.2 130.1
115.4 115.1 115.1
160.9
108.2
160.6
147.0
112.3
127.0
120.4
130.1
115.1
68.9
160.9 160.9 160.7 161.0 161.1
108.1 108.1 108.2 107.9 108.0
160.7 160.7 160.4 161.1 161.0
146.5 146.5 148.3 141.2 144.5
112.3 112.3 112.4 112.2 112.2
127.0 127.0 127.0 127.2 127.0
120.5 120.5 120.4 120.4 120.5
130.2 130.2 130.0 130.3 130.3
115.1 115.1 115.0 115.2 115.2
3
4
5
7
8
1',8'
2',7'
3',6'
4',5'
9'
68.8
68.8
68.8
68.9
68.9
68.8
68.5
69.0
138.6 138.6 138.6
111.0 111.4 111.4
138.6
111.4
130.3
(d, 1.5)
129.1
(d, 9.0)
116.0
(d, 22.5)
163.3
(d, 247.5)
138.6 138.6 138.6 138.5 138.6
111.3 111.3 111.6 110.7 111.1
4'a,10'a
8'a,9'a

133.7 131.0
132.9 132.9 126.2 130.0 139.7
128.5 128.7 128.6 133.6 127.8
129.0 131.9 114.3 129.0 124.1
135.1 124.0 161.2 131.4 148.1
1''
2'',6''
3'',5''
4''

126.9 126.9

128.9 129.4

130.6 140.6
a124.4 (C-1'',8''), 127.1 (C-2'',7''), 130.3 (C-3'',6''), 129.7 (C-4'',5''), 134.4 (C-9''), 122.8 (C-8a'',9a''), 148.1 (C-4a'',10a''); b21.0
(CH3); c55.3 (OCH3).
TABLE 4
15N NMR chemical shifts (, ppm, DMSO-d6) for derivatives 5a–i.
5a
5b
5c
5d
5e
5f
5g
5h
5i
No N
δN
-174.2 -180.0 -180.4 -180.2 -179.9 -179.9 -180.7 -178.0 -178.5
-52.9 -71.1 -73.5 -71.5 -69.5 -69.5 -76.7 -56.3 -62.0
1
6
-283.6 -283.9 -283.9 -283.7 -283.0 -283.9 -284.0 -283.8 -284.5
-66.9
10'
10''
NO2















-10.6

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TABLE 5
Comparison of the 1H NMR chemical shifts (, ppm, DMSO-d6) for derivatives 5b,g with already published results.
AMTAC-
01
C(AMTAC-01) –
C(5b)
C(AMTAC-02) –
C(5g)
5b
this work
5g
AMTAC-02
ref. 15
5b
this work
AMTAC-01
ref. 15
5g
AMTAC-02
ref. 15
No
this work
this work
ref. 15
δH (mult, J, Hz)
8.55 (s)


8.40 (s)

δC
this work
ref. 15
8
9
11
12
10
8.54


8.38

8.52 (s)


8.42 (s)

8.50


8.40

160.8
108.2
160.6
147.6
112.3
161.30 (0.5)
112.81
161.30 (0.7)
148.05 (0.45) 0.45
108.60
0.5
0.7
160.7
108.2
160.4
148.3
112.4
161.17 (0.47)
112.87
161.70 (1.3)
148.78 (0.48)
108.65
0.47
0.48
3
4
5
7
8
7.00 (dd,
8.2, 1.4)
6.84 (ddd,
8.2, 7.2, 1.4)
7.28 (ddd,
8.2, 7.2, 1.4)
7.02 (dd,
8.2, 1.4)

6.98 (dd,
8.2, 1.0)
6.84 (ddd,
8.2, 7.1, 1.0)
7.27 (ddd,
8.4, 7.1, 1.3)
7.01 (dd,
8.1, 1.3)

5
4
3
2
7.02
6.82
7.26
7.00
7.02
6.82
7.26
6.88
127.0
120.4
130.2
115.44
127.0
120.4
130.0
115.52
1',8'
2',7'
3',6'
4',5'
0.49
0.44
0.52
-0.19
0.5
120.89 (0.49)
120.84 (0.44)
130.52 (0.52)
0.43
130.63 (0.43)
115.1
68.8

138.6
111.4
133.7
127.50
69.24
115.0
68.8

138.6
111.6
126.2
114.81 (-0.19)
69.30 (0.5)
7
18
1
6
13
9'
10'
4'a,10'a
8'a,9'a
1''

9.82




9.79



9.83 (s)
9.79 (s)
0.51
0.41
0.35
0.4
0.48
0.44
139.11 (0.51)
111.81 (0.41)
134.05 (0.35)
139.08 (0.48)
112.04 (0.44)
129.02






7.32 (app d,
8.9)
6.89 (app d,
8.9)

3.73 (s)
14
7.35 (ma)
7.36
6.99
126.9
128.9
127.30 (0.4)
131.08
128.6
114.3
126.80
129.06
2'',6''
3'',5''
15,16
17
7.35 (ma)
7.35
7.31
7.35 (ma)

7.33

130.6

129.33

161.2
55.3
160.86 (-0.34)
55.76 (0.46)
-0.34
0.46
4''
OCH3

3.71
aoverlapped
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TABLE 6
1H,13C-HMBC correlations for derivatives 5b and 5g.
5b
5g
No
δH (mult, J, Hz)
HMBC correlations
68.8 (C-9'), 112.3 (C-8), 160.6 (C-
5), 160.8 (C-3)
δH (mult, J, Hz) HMBC correlations
68.8 (C-9'), 112.4 (C-8), 160.4 (C-5), 160.7
8.55 (s)
8.52 (s)
8.42 (s)
3
(C-3)
126.9 (C-2'',6''), 133.7 (C-1''), 147.6
(C-7)
8.40 (s)
128.6 (C-2'',6''), 126.2 (C-1'')
7
7.00 (dd,
68.8 (C-9'), 130.2 (C-3',6'), 138.6
(C-4'a,10'a)
6.98 (dd,
68.8 (C-9'), 130.0 (C-3',6'), 138.6 (C-4'a,10'a)
1',8'
2',7'
3',6'
4',5'
10'
8.2, 1.4)
8.2, 1.0)
6.84 (ddd,
8.2, 7.2, 1.4)
7.28 (ddd,
8.2, 7.2, 1.4)
7.02 (dd,
6.84 (ddd,
8.2, 7.1, 1.0)
7.27 (ddd,
8.4, 7.1, 1.3)
7.01 (dd,
111.6 (C-8'a,9'a), 115.0 (C-4',5'), 127.0 (C-
1',8', w)
111.4 (C-8'a,9'a), 115.1 (C-4',5')
127.0 (C-1',8'), 138.6 (C-4'a,10'a)
127.0 (C-1',8'), 138.6 (C-4'a,10'a)
111.6 (C-8'a,9'a), 120.4 (C-2',7')
68.8 (C-9', w), 111.4 (C-8'a,9'a),
120.4 (C-2',7')
8.2, 1.4)
8.1, 1.3)
111.4 (C-8'a,9'a), 115.1 (C-4',5'),
138.6 (C-4'a,10'a, w)
130.6 (C-4''), 147.6 (C-7)
133.7 (C-1'')
111.6 (C-8'a,9'a), 115.0 (C-4',5'), 138.6 (C-
9.83 (s)
9.79 (s)
4'a,10'a, w)
7.35 (ma)
7.35 (ma)
7.35 (ma)
7.32 (d, 8.9)
6.89 (d, 8.9)

128.6 (C-2'',6''), 148.3 (C-7), 161.2 (C-4'')
2'',6''
3'',5''
4''
114.3 (C-3'',5''), 126.2 (C-1''), 161.2 (C-4'', w)


3.73 (s)
161.2 (C-4'')
OCH3


aoverlapped
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Figure 1: PRISMA flow diagram of included/excluded studies
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