Efficient Access to Chromeno[4,3- b ]quinolines Related to Dependensin

Article abstract of DOI:10.1055/s-0036-1589087

We report a robust synthesis of novel chromeno[4,3- b ]quinoline derivatives structurally similar to the natural product dependensin. The target compounds are accessed through the acid-catalysed condensation of 2-aminoacetophenones or 2-aminochalcones with substituted flavanones, which are in turn obtained from 2-hydroxyacetophenones and benzaldehydes.

Full text of DOI:10.1055/s-0036-1589087

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
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J. C. Dobrowolski et al.
Letter
Synlett
Efficient Access to Chromeno[4,3-b]quinolines Related to Depen-
densin
Jeremy C. Dobrowolskia
Chromeno[4,3-b]quinoline
Dependensin
Benjamin H. Fraserb
Mohan Bhadbhadec
David StC. Blacka
Naresh Kumar*a
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a School of Chemistry, The University of New South
Wales Australia, NSW 2052, Australia
n.kumar@unsw.edu.au
b The Australian Nuclear Science and Technology
Organisation, Kirrawee DC, NSW 2232, Australia
c Solid State & Elemental Analysis Unit, Mark
Wainwright Analytical Centre, Division of Research,
UNSW Australia, NSW 2052, Australia
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Received: 09.05.2017
Accepted after revision: 28.06.2017
Published online: 08.08.2017
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DOI: 10.1055/s-0036-1589087; Art ID: st-2017-d0344-l
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Abstract We report a robust synthesis of novel chromeno[4,3-b]quin-
oline derivatives structurally similar to the natural product dependen-
sin. The target compounds are accessed through the acid-catalysed
condensation of 2-aminoacetophenones or 2-aminochalcones with
substituted flavanones, which are in turn obtained from 2-hydroxyace-
tophenones and benzaldehydes.
O
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Dependensin
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Key words dependensin, chromeno[4,3-b]quinoline, flavanone, acid-
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catalysed synthesis
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O
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Dimeric flavonoid compounds are widely distributed in
nature and show a range of anti-inflammatory, antioxidant,
anticancer, and antiviral activities.1 Dependensin, a dimeric
flavonoid isolated from the root bark of the Tanzanian me-
dicinal plant, Uvaria dependens, has been of particular in-
terest to medicinal chemists due to its potent antimalarial
activity.2 Extensive research has been conducted into vary-
ing the substituents appended to the heterocyclic core of
dependensin, whilst conserving the styryl functionality
and the trimethoxy substitution pattern present on the two
chromane rings.3,4
Meanwhile, the [1,6]naphthyridine moiety has been
previously explored for its drug-like properties,5 including
antiviral and anticancer activities.6,7 The [1,6]naphthyri-
dine moiety resembles the central pyrano[4,3]pyran system
of dependensin, except with nitrogen replacing the two ox-
ygen atoms in the latter ring system. The effect on biologi-
cal activity of changing the two heterocyclic oxygen atoms
of dependensin to nitrogen is yet to be explored. Moreover,
structures that feature one of each heteroatom (oxygen and
nitrogen) in the central heterocyclic core would be an inter-
esting hybrid between dependensin and [1,6]naphthyri-
dine-based scaffolds (Figure 1).
N
H
O
Chromeno[4,3-b]quinoline
[1,6]Naphthyridine
Figure 1 Comparison between lead scaffolds and dependensin
The synthesis of such hybrid chromeno[4,3-b]quinoline
derivatives would allow for an evaluation of the effect of ni-
trogenation on the antimalarial activity of dependensin and
would also facilitate the development of key structure–
activity relationships (SAR) surrounding this class of com-
pounds.
Previously, different strategies have been reported for
the synthesis of benzopyranobenzopyran compounds relat-
ed to dependensin as well as their [1,6]naphthyridine de-
rivatives.3,8–11 For example, an early work by Mao and co-
workers described the synthesis of [1,6]naphthyridines us-
ing an expensive Sc(OTf)3 catalyst.8 However, their reaction
was limited to the use of 2-aminoacetophenones. Ravi and
co-workers recently demonstrated a green chemistry meth-
od for the synthesis of 6-phenyl-7-styryl-5,6-dihydrodi-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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J. C. Dobrowolski et al.
Letter
Synlett
benzo[b,h][1,6]naphthyridines via homodimerisation of
2′-aminochalcones using sodium dodecyl sulfate.9 However,
their work only investigated substitution at the pendant
phenyl and styryl groups, which was achieved through the
use of different substituted benzaldehydes. Additionally,
our group has synthesised [1,6]naphthyridine derivatives of
dependensin via a propylphosphonic anhydride solution
(T3P®)-catalysed reaction, which allowed a range of modifi-
cations around both the pendant phenyl group and the
chromane ring system.11
The total synthesis of dependensin itself was first re-
ported by our group in 2007 in a seven-step synthesis start-
ing from 3,4,5-trimethoxyphenol.10 We subsequently
demonstrated the promising antimalarial activity of a small
selection of dependensin derivatives that were modified at
the styryl and pendant phenyl groups.3 These works sup-
port the interest surrounding the core dependensin scaffold
and in the development of novel dependensin derivatives
that might show enhanced biological properties. However,
to date no studies have reported the synthesis of mixed ox-
ygen–nitrogen heterocyclic scaffolds (specifically, pyra-
no[4,3]pyridine) that also feature the trimethoxy-substitut-
ed aromatic ring system and the styryl functionality found
in dependensin.
methanolic or isopropanolic hydrochloric acid to give a
range of phenyl-substituted flavanones 4.
Due to the lack of cost effective commercial sources, the
2′-hydroxy-3′,4′,6′-trimethoxyacetophenone was synthe-
sised by reaction of 3,4,5-trimethoxyphenol with methyl
iodide to give 1,3,4,5-tetramethoxybenzene, which was fur-
ther acetylated using acetyl chloride and aluminum chlo-
ride catalyst to give the corresponding acetophenone 1
(where R = OCH3).9
We employed the Friedländer methodology to couple
the substituted flavanones 4 with a range of 2′-aminoace-
tophenones 10 or 2′-aminochalcones 11 catalysed by T3P®,
giving the targeted 6-phenylchromeno[4,3-b]quinoline
compounds 12 and 6-phenyl-7-styryl-6H-chromeno[4,3-
b]quinoline 13, respectively (Scheme 2). Reactions were ro-
bust and not air or water sensitive, with a simple and
straightforward workup procedure. Compounds 12 and 13
had yields ranging from 30–79% and 23–48%, respectively,
and were crystallised/precipitated from methanol to give
pure products, without the need for chromatography.
R1
O
R1
O
Our approach is significant in the way that it bridges the
gap between the nitrogen-containing dibenzo[1,6]naph-
thyridine scaffold and the oxygen-containing benzopyrano-
benzopyran scaffold seen in dependensin. We have devel-
oped a methodology for the synthesis of mixed tetrahetero-
cyclic-fused systems in which one heteroatom is oxygen
and the other nitrogen. Our novel hybrid compounds fea-
ture diverse substitution around the core phenylchrome-
no[4,3-b]quinoline scaffold, drawing close structural simi-
larities to dependensin.
R1
R2
4
R5
O
O
R5
R4
T3P® (50% EtOAc)
80 °C, 24 h
R3
NH2
R5
NH2
10
11
R6
R5
R4
R5
R5
R1
N
O
R1
N
O
Our synthetic strategy begins with the reaction of 2′-hy-
droxyacetophenones 1 with benzaldehydes 2 under basic
conditions to give 2′-hydroxychalcones 3 (Scheme 1). These
chalcones are further cyclised in the presence of either
R3
R1
R1
R6
R1
R2
R1
R2
12
13
Scheme 2 Synthesis of target 6-phenylchromeno[4,3-b]quinoline de-
rivatives 12 and 13
O
R1
O
R1
O
Notably, compounds 13 also contain the styryl substitu-
ent found in dependensin. In particular, the hexamethoxy
compound 13l is a closely related analogue of dependensin.
Evidence for the formation of 13l was seen through exam-
ination of the 2D HSQC and HMBC NMR (DMSO-d6) spectra,
which showed the appearance of a 13C NMR signal at δ =
105.0 ppm that was attributed to the new styrene function-
al group as well as the hexamethoxy 1H NMR and 13C NMR
signals at δ = 3.49, 3.66, 3.81, 3.87, 3.89, 4.01 ppm and δ =
60.1, 60.1, 55.3, 60.4, 56.5, 55.6 ppm, respectively. The CH
proton changes from a doublet of doublets in the starting
flavanone 4 to a singlet in the final products (12, 13). Analy-
R2
2
R1
OH
R2
R1
OH
KOH
R1
R1
EtOH, H2O
8 h, reflux
Yield: 90–95%
1
3
R1
O
O
MeOH/IPA
concd HCl
48 h, reflux
R1 = H, OCH3
R2 = H, Br, Cl, OCH3
R1
R1
R2
Yield: 63–84%
4
Scheme 1 Synthesis of substituted flavanone intermediates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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J. C. Dobrowolski et al.
Letter
Synlett
sis of the HRMS spectrum supported the proposed molecu-
lar formula of C36H34NO7 [M + H], with a molecular ion peak
at m/z = 592.2333 (expected m/z = 592.2330). Overall, a di-
verse range of 6-phenylchromeno[4,3-b]quinoline ana-
logues was synthesised (see Table 1 for 12 and Table 2 for
13).
Table 2 6-Phenyl-7-styryl-6H-chromeno[4,3-b]quinoline Derivatives
13 Produced via Scheme 2
Product
R1
R2
R5
R6
Yield (%)
13a
13b
13c
13d
13e
13f
13g
13h
13i
H
H
H
H
42
37
47
34
43
43
42
43
48
41
37
23
H
H
H
Br
Cl
H
H
H
H
Table 1 6-Phenylchromeno[4,3-b]quinoline Derivatives 12 Produced
via Scheme 2
H
Br
Br
Br
Cl
Cl
Cl
H
H
H
H
Br
Cl
H
Product
R1
R2
R3
CH3
R4
Yield (%)
H
H
H
H
12a
12b
12c
12d
12e
12f
H
H
H
30
63
58
31
57
50
54
36
79
74
72
51
55
59
46
42
51
H
H
Br
Cl
H
H
Br
Cl
CH3
H
H
H
H
CH3
H
13j
H
OCH3
OCH3
OCH3
H
OCH3
H
CH3
H
13k
13l
H
Cl
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
H
OCH3
H
H
Br
Cl
H
12g
12h
12i
H
H
H
OCH3
H
H
Reactions generating 6-phenyl-7-styryl-6H-chrome-
no[4,3-b]quinoline derivatives 13 gave yields below 50%,
which was due to incomplete consumption and recovery of
starting material. 1,3,4,8,9,10-Hexamethoxy-6-phenyl-7-
styryl-6H-chromeno[4,3-b]quinoline 13l was crystallised
from methanol to yield crystals suitable for single-crystal
X-ray diffraction. A perspective view of the dependensin
derivative3 and an ORTEP representation of 13l in a similar
orientation are shown in Figure 2.
In the above comparison, 1,3,4,8,10,11-hexamethoxy-6-
(4-methoxyphenyl)-7-(4-methoxystyryl)-6a,12a-dihydro-
6H,7H-chromeno[4,3-b]chromene synthesised by Deva-
karam and co-workers has an sp3 carbon at C6 on the chro-
H
Cl
Cl
Cl
Br
Br
H
12j
H
Br
Cl
12k
12l
H
H
H
12m
12n
12o
12p
12q
H
Cl
CH3
OCH3
OCH3
OCH3
OCH3
H
CH3
H
CH3
Br
H
H
C6H5
C6H5
H
Cl
Figure 2 (a) X-ray structure of dependensin derivative;3 (b) ORTEP diagram of compound 13l with atom labelling (thermal ellipsoids are drawn at 50%
probability level).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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J. C. Dobrowolski et al.
Letter
Synlett
mane ring and a 7-styryl functionality which gives the
molecule a folded conformation. This is contrasted by
1,3,4,8,9,10-hexamethoxy-6-phenyl-7-styryl-6H-chromeno-
[4,3-b]quinoline 13l which features an sp2 carbon at this
position, due to the quinoline ring system which gives the
molecule a planar conformation.
The carbon atoms C6 and C8 (equivalently marked in
Figure 2) are significant points that are mainly responsible
for the overall change in the molecular envelopes as depict-
ed in Figure 3. The dependensin derivative3 (orange) is
buckled with its two substituents pointing above and below
the average plane of the molecule, whereas compound 13l
(purple) shows overall planarity (as can be expected with
the presence of aromatic rings) with both the substituents
pointing in the same direction.
References and Notes
(1) Nianhuan, Y.; Aiming, S.; Xiaobing, W.; Seth, D.; Kit, S. L. J. Comb.
Chem. 2007, 9, 668.
(2) Nkunya, M.; Waibel, R.; Achenbach, H. Phytochemistry 1993, 34,
853.
(3) Devakaram, R.; Black, D. StC.; Andrews, K. T.; Fisher, G. M.;
Davis, R. A.; Kumar, N. Bioorg. Med. Chem. 2011, 19, 5199.
(4) Devakaram, R.; Black, D. StC.; Choomuenwai, V.; Davis, R. A.;
Kumar, N. Bioorg. Med. Chem. 2012, 20, 1527.
(5) Zeng, L.-F.; Wang, Y.; Kazemi, R.; Xu, S.; Xu, Z.-L.; Sanchez, T.
W.; Yang, L.-M.; Debnath, B.; Odde, S.; Xie, H. J. Med. Chem.
2012, 55, 9492.
(6) Bedard, J.; May, S.; L’Heureux, L.; Stamminger, T.; Copsey, A.;
Drach, J.; Huffman, J.; Chan, L.; Jin, H.; Rando, R. F. Antimicrob.
Agents Chemother. 2000, 44, 929.
(7) Suresh, T.; Kumar, R. N.; Mohan, P. Asian J. Chem. 2003, 15, 855.
(8) Mao, D.; Tang, J.; Wang, W.; Liu, X.; Wu, S.; Yu, J.; Wang, L. Org.
Biomol. Chem. 2015, 13, 2122.
(9) Ravi, M.; Chauhan, P.; Singh, S.; Kant, R.; Yadav, P. P. RSC Adv.
2016, 6, 48774.
(10) Deodhar, M.; Black, D. StC.; Kumar, N. Tetrahedron 2007, 63,
5227.
(11) Dobrowolski, J. C.; Katen, A.; Fraser, B. H.; Bhadbhade, M.; Black,
D. StC.; Kumar, N. Tetrahedron Lett. 2016, 57, 5442.
(12) Representative Procedure for the Preparation of 12q
To
a mixture of 5,7,8-trimethoxy-2-phenylchroman-4-one
(0.16 mmol, 0.050 g) and 2′-amino-5-chlorobenzophenone
(0.16 mmol, 0.037 g) was added T3P®in 50% EtOAc (0.32 mmol,
0.102 g), and the reaction mixture was stirred at 80 °C for 24 h.
Water (25 mL) was added to dissolve the T3P®and the mixture
was extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were washed with brine, dried over Na2SO4 filtered,
and the solvent removed under reduced pressure. The crude
product was recrystallised from MeOH to give a white solid. The
white solid was filtered and dried to give pure 12q (51%); mp
222–223 °C. 1H NMR (600 MHz, DMSO-d6): δ = 8.09 (d, J = 9.0
Hz, 1 H), 7.80 (dd, J = 9.0, 2.4 Hz, 1 H), 7.65–7.61 (m, 1 H), 7.51
(ddt, J = 8.7, 7.5, 1.2 Hz, 2 H), 7.36 (tt, J = 7.6, 0.9 Hz, 1 H), 7.24–
7.18 (m, 4 H), 7.10–7.00 (m, 3 H), 6.43 (d, J = 3.4, Hz, 1 H), 6.19–
6.15 (m, 1 H), 3.91 (s, 3 H), 3.83 (s, 3 H), 3.53 (s, 3 H).13C NMR
(151 MHz, DMSO): δ = 155.2, 149.2, 149.0, 146.0, 143.2, 137.6,
133.6, 131.9, 131.3, 130.8, 130.5, 130.3, 129.8, 128.9, 128.6,
128.4, 128.1, 127.4, 126.3, 124.5, 124.3, 124.0, 107.2, 93.1, 75.5,
60.3, 56.5, 55.5. IR (ATR): νmax = 3035, 2929, 2833, 2340, 2102,
1752, 1571 cm–1. HRMS (ESI+, 47 V): m/z calcd for C31H25ClNO4
[M + H]: 510.1467; found: 510.1468.
Figure 3 Difference in the 3D envelope of the two molecules
Previously, studies have described the strong fluores-
cence of [1,6]naphthyridine analogues similar to the target-
ed structures.8,11 However, the synthesised 6-phenylchrom-
eno[4,3-b]quinoline derivatives did not show fluorescence,
possibly due to the oxygen not being able to transfer charge
to the quinoline moiety.
In summary, we have developed a robust and efficient
methodology for the synthesis of a new class of 6-phenyl-
chromeno[4,3-b]quinoline compounds that share close
structural similarities with the antimalarial natural prod-
uct, dependensin.12–14 Our strategy only requires five steps
for total synthesis and gives reasonable to high yields with
limited chromatographic steps. The biological properties of
the synthesised compounds will be reported in due course.
(13) Representative Procedure for the Preparation of 13l
To a mixture of 5,7,8-trimethoxyflavanone (0.16 mmol, 0.050 g)
and 2′-amino-4,5,6-trimethoxychalcone (0.16 mmol, 0.050 g)
was added T3P®in 50% EtOAc (0.32 mmol, 0.102 g), and the
reaction mixture was stirred at 80 °C for 24 h. Water (25 mL)
was added to dissolve the T3P®and the mixture was extracted
with CH2Cl2 (3 × 20 mL). The combined organic extracts were
washed with brine, dried over Na2SO4 filtered, and the solvent
removed under reduced pressure. The crude product was
recrystallised from MeOH to give a yellow crystalline solid. The
yellow solid was filtered and dried to give pure 13l (23%); mp
115–116 °C. 1H NMR (600 MHz, DMSO-d6): δ = 7.72 (dd, J = 16.7,
3.2 Hz, 1 H), 7.36–7.33 (m, 2 H), 7.29–7.27 (m, 7 H), 7.18 (dd, J =
5.1, 2.6 Hz, 2 H), 6.70 (d, J = 6.0 Hz, 1 H), 6.40 (d, J = 4.0 Hz, 1 H),
6.11 (d, J = 16.6 Hz, 1 H), 4.01 (s, 3 H), 3.88 (d, J = 14.3 Hz, 6 H),
3.82 (s, 3 H), 3.67 (s, 3 H), 3.49 (s, 3 H).13C NMR (151 MHz,
Funding Information
We thank the Australian Research Council (ARC) Grant DP140102195
for their financial support. JCD thanks University of New South Wales
for an Australian Postgraduate Award (APA)
A
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Research
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Acknowledgment
We thank the NMR and BMSF facility, University of New South Wales.
We also thank the University of New South Wales for their facilities
and support in this project.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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J. C. Dobrowolski et al.
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DMSO): δ = 155.1, 154.8, 154.6, 148.6, 141.9, 131.9, 131.2,
128.4, 127.9, 127.8, 125.8, 125.6, 125.6, 105.0, 93.0, 75.7, 60.5,
60.4, 60.1, 56.5, 55.6, 55.3. IR (ATR): νmax = 3749, 2928, 2298,
1913, 1559 cm–1. HRMS (ESI+, 47 V): m/z calcd for C36H34NO7
[M + H]: 592.2330; found: 592.2333.
M165Z), mounted on a MicroMount (MiTeGen, USA) consisting
of a thin polymer tip with a wicking aperture. Crystallographic
data excluding structure factors have been deposited with the
Cambridge Crystallographic Data Centre as supplementary pub-
lication; number CCDC 1548511. A copy of the data can be
obtained free of charge from CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK or e-mail: deposit@ccdc.cam.ac.uk.
(14) X-ray Crystallography
A suitable single-crystal of 13l (CCDC 1548511), obtained from
methanol, was selected under a polarizing microscope (Leica
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E