Tetrahedron 70 (2014) 8480e8487

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Tetrahedron
journal homepage: www.elsevier.com/locate/tet

Indium catalyzed solvent-free multicomponent synthesis

of cytotoxic dibenzo[a,h]anthracenes from aldehydes,
2-hydroxy-1,4-naphthoquinone, and 2-naphthol
Idaira Hueso-Falco


n a, Angel
pez-Rodríguez a,
Amesty a, Patricia Martín b, Matías Lo
Leandro Ferna
ndez-Pe b
vez-Braun

rez , Ana Este a,*

a
nica Antonio Gonza

Instituto Universitario de Bio-Orga
lez (CIBICAN), Departamento de Química Orga
nica, Universidad de La Laguna,

nchez 2, 38206 La Laguna, Tenerife, Spain
Avda. Astrofísico Fco. Sa
b
Departamento de Ciencias Clínicas-Unidad de Farmacología, Facultad de Ciencias de la Salud, Universidad de Las Palmas de Gran Canaria,
Unidad Asociada de Biomedicina ULPGC-IIBM “Alberto Sols”-CSIC, Las Palmas de Gran Canaria, Spain

a r t i c l e i n f o a b s t r a c t

Article history: A series of dibenzo[a,h]anthracene derivatives were synthesized through a straightforward, one-pot
Received 4 August 2014 protocol based on a three-component reaction with 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes,
Received in revised form 22 September 2014 and 2-naphthol as synthetic inputs, using InCl3 a catalyst under solvent-free conditions. Most of the
Accepted 23 September 2014
obtained ortho-quinonic adducts were cytotoxic against HEL and MCF-7 tumoral cell lines.
Available online 28 September 2014
Ó 2014 Elsevier Ltd. All rights reserved.

Keywords:
Multicomponent reaction
Indium trichloride
Naphthoquinone
Cytotoxicity

1. Introduction reported.3 A facile, one-pot, pseudo four-component catalyst- and

Multicomponent reactions (MCRs) are one-pot reactions
employing more than two starting materials, where most of the
atoms of them are incorporated in the final product. Several de-
scriptive tags are regularly attached to MCRs: they are atom eco-
nomic, efficient since the product is formed in one-step, they are
also convergent and exhibit a very high bond-forming-index (BFI).
Furthermore, the rapid and easy access to biologically relevant
compounds by MCRs, and its scaffold diversity has been recognized
by the synthetic community in industry and academia, as a pre-
ferred method to design and discover small molecular weight
compounds with biological activity.1
Quinones and b-naphthols are considered privileged structures2
since they are occurring fragments in natural products and drugs
exhibiting a broad spectrum of biological activities. Both structures
have been involved in different MCRs. For example, the preparation
of Betti bases by the three-component reaction of aromatic aldehyde,
2-naphthol, and acetonitrile (or benzamide) catalyzed by 1-methyl-
3-(2-(sulfooxy)ethyl)-1H-imidazol-3-ium has been recently
* Corresponding author. Tel./fax: þ34 922318576; e-mail address: aestebra@ull.es

vez-Braun).
(A. Este
solvent-free synthesis of novel benzopyrano[2,3-b] pyridines was
achieved through the reaction of salicylaldehyde, naphthols, and
malononitrile.4 Several xanthene derivatives have been also obtained
using a variety of hydroxynaphthols such as 2-naphthol, 2,7-
dihydroxy-naphthalene, and 2,6-dihydroxynaphthalene, which re-
act with aldehydes, and 2-hydroxynaphthalen-1,4-dione using cat-
alytic sulfuric acid in water under reflux to yield a variety of dibenzo
[a,i]xanthene-diones.5
With respect to the quinones, our research group has carried out
several multicomponent reactions using 2-hydroxy-1,4-quinone
moiety in order to obtain antitumoral and antibacterial compounds
based on quinone cores fused to heterocyclic rings.6 In our approach
2-hydroxy-1,4-quinone moiety is employed as an adequate synthetic
equivalent to a 1,3-dicarbonyl compound. In this case, the Knoeve-
nagel condensation with aldehydes leads to a reactive intermediate
quinone methide (QM),7 which is susceptible to be trapped by diverse
electron rich alkenes as dienophiles via hetero DielseAlder reac-
tions,6aed or reacts with diverse nucleophiles via Michael addition.6eeg
As part of an ongoing development of efficient protocols for the
preparation of substituted heterocyclic quinones, and in a contin-
uation of our work on MCRs, we report the preparation of dibenzo
[a,h]anthracenes. These crossed adducts were prepared using

http://dx.doi.org/10.1016/j.tet.2014.09.076
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

n et al. / Tetrahedron 70 (2014) 8480e8487
I. Hueso-Falco 8481

nucleophiles as privileged structures such as the mentioned 2-
hydroxy-1,4-naphthoquinone and b-naphthol, in the presence of
aldehydes and indium trichloride as catalyst under solvent-free
conditions. The obtained dibenzo[a,h]anthracenes were tested for
their antiproliferative activity against two tumoral cell lines, and
some of them resulted to be highly active.
2. Results and discussion
In the presence of an aldehyde both 2-hydroxy-1,4-
naphthoquinone (1) and 2-naphthol (2) can react to afford the
corresponding quinone methide intermediate (Fig. 1).
(1.1 equiv) in the presence of 10 mol % of EDDA and EtOH as
solvent under reflux, but we found that the naphthoquinone di-
mer (6) was quantitatively formed instead of the desired adduct.
Similar results were obtained with other aldehydes such as
benzaldehyde, or 3-pyridylcarboxaldehyde. These dimers are
obtained from the nucleophilic attack of 2-hydroxy-1,4-
naphthoquinone instead of 2-naphthol on the quinone methide
intermediate (Scheme 2).
Since the ortho-quinonic adducts are analogues of b-lapachone,
an antitumoral compound, which is currently in multiple phase II
clinical trials, and based on our previous pharmacophore modeling
of pyranonaphthoquinones, which indicated that an extension of

O O R1
1
OH O OH
O
+ RCHO RCHO +
3 R

1 O O 2
(I) (II)

Fig. 1. Quinone methide intermediates from 2-hydroxy-1,4-naphthoquinone (1) and from 2-naphthol (2).

In order to explore, which one shows the highest nucleophilicity
we calculated the Fukui function, which is one of the widely used
local density functional descriptor to model chemical reactivity and
site-selectivity.8 The local (condensed) Fukui functions ðfkþ ; fk ; fk0 Þ
are calculated using the procedure proposed by Yang and Mortier,9
employing equations such as fkþ ¼ ½qðN þ 1Þ  qðNÞ for nucleo-
philic attack; fk ¼ ½qðNÞ  qðN  1Þ for electrophilic attack, and
fk0 ¼ 1=2½qðN þ 1Þ  qðN  1Þ for radical attack, where N is the
total number of electrons present. When a molecule accepts elec-
trons, the electrons tend to go to places where fkþ is large because it
is at these locations that the molecule is most able to stabilize
additional electrons. Therefore a molecule is susceptible of a nu-
cleophilic attack at sites where fkþ is large. The calculated values of
the Fukui function (f) indicated that the highest value for 2-
naphthol (2) was located at C-1 ðfk ¼ 0:22Þ, while for 2-hydroxy-
naphthoquinone the highest value was located at C-3 ðfk ¼ 0:32Þ.
From these results the reactive intermediate methylenquinone is
presumably formed from 2-hydroxy-1,4-naphthoquinone.
The intermediate (I) contains two a,b-unsaturated carbonyl
systems, which are susceptible to be attacked by the 2-naphthol,
yielding ortho- or para-quinonic adducts after cyclization and loss
of water (Scheme 1).
the structure through the pyran ring produces high cytotoxicity,10
we decided to obtain these interesting adducts using other cata-
lysts employed in multicomponent reactions of 1,3-dicarbonyl
compounds such as Yb(OTf)3,11 PTSA,12 CAN,13 InCl314 or
Sc(OTf)3.15 On the other hand, solvent-free conditions for hetero-
cyclic synthesis have increased rapidly in recent years, because
many protocols based on cyclocondensation reactions may offer
distinct advantages such as, improved atom utilization by avoid-
ance of common derivation procedures, decreased byproduct for-
mation, and decreased waste.16 Thus we decided to study the
reaction of 2-hydroxy-1,4-naphthoquinone, 2-naphthol, and 4-
bromo-benzaldehyde using the mentioned catalysts without sol-
vent at 120  C. The obtained results are shown in Table 1.
In all entries only the desired ortho-quinonic adduct was
regioselectively obtained since no traces of dimers or para-quinonic
adducts were detected. The structure of this compound was thor-
oughly determined by NMR studies being very helpful the analysis
of the HMBC correlations to discriminate between ortho and para
adducts. Furthermore the structure of compound (4a) was also
ratified by X-ray (Fig. 2).
The best yield was obtained using 30 mol % of InCl3 for 3 h (Table
1, entry 5). It was found that no conversion was obtained even 4 h of

O O
O
OH OH O
O O
b b)
+ + R
R H

O O a O R

1 2 3 a) para quinonic adduct (5)

O
O

ortho quinonic adduct (4)

Scheme 1. Formation of ortho- and para-quinonic adducts.

In our previous works we have found that EDDA (ethylendi-
amine diacetate) is an appropriate catalyst in the Knoevenagel
condensation of 2-hydroxy-1,4-quinones and aldehydes.6 Thus we
decided to carry out the multicomponent reaction from lawsone
(1), 2-naphthol (2) (1.1 equiv), and 4-bromobenzaldehyde (3a)
heating. Higher percentage loading of the catalyst neither increased
the yield nor lowered the reaction time. We also tried to improve
the yield carrying out the multicomponent reaction with 30 mol %
of InCl3 in the presence of MW irradiation under different condi-
tions but in all cases lower yields were obtained.
8482
n et al. / Tetrahedron 70 (2014) 8480e8487
I. Hueso-Falco

Scheme 2. Formation of naphthoquinone dimer (6).

Table 1
Reaction conditions for the formation of compound 4a
O O
OH CHO 11
OH O Br
Catalyst 12
+ +
14 3'
Br neat, 120 ºC 7a 1'
O O
1 2 3c 4a 6a
6
5

Entry Catalyst (mol %) Time (h) Yielda (%)

1 Yb(OTf)3 (20)
2 CAN (30)
3 InCl3 (20)
4 InCl3 (30)
5 InCl3 (30)
6 InCl3 (30)
7 PTSA (60)
8 Yb(OTf)3 (20)
9 Yb(OTf)3 (30)
10 Sc(OTf)3 (30)
a
Isolated yield.
2 61
3 27
3 48
2.5 70
3 73
4 73
2 15
3 59
3 62
3 57

Table 2
Scope of the reaction with aldehydes (3)
O InCl3 O
OH OH (30 mol %) O
+ + RCHO
neat, 120 ºC R

O O
1 2 3 4

Entry R Compound Yielda (%)

1 4-BrePh 4a 73
2 Ph 4b 70
3 4-NO2ePh 4c 66
4 4-ClePh 4d 74
5 4-FePh 4e 46
6 2-FePh 4f 67
7 2-Thienyl 4g 25
8 3-Pyridyl 4hþ5h 59b
Fig. 2. X-ray crystal structure of compound 4a. 9 2,4,5-Trimethoxyphenyl 4iþ5i 14c
10 3,4-Methylenedioxyphenyl 4jþ7j 41d
a
Thus, we selected the conditions of entry 5 in Table 1 in order to Isolated yields.
b
analyze the formation of this adduct by using of other aldehydes. Ratio 4h/5h 9.8:1.0.
c
Ratio 4i/5i 1:1.
Various heteroaromatic aldehydes and mono-, di-, and tri- d
Ratio 4j/7j 4.4:1.0.
substituted aromatic aldehydes containing both electron-
withdrawing and electron-donating substituents were used and
the obtained results are shown in Table 2. When we carried out the multicomponent reaction from 4-
When aliphatic aldehydes such as paraformaldehyde, propanal bromo-benzaldehyde, 7-methoxy-naphthalen-2-ol, and lawsone,
or ethyl glyoxylate were employed we did not detect the formation using the same reaction conditions the corresponding ortho adduct
of ortho-quinonic adducts (4). As we can see in most of cases (en- was obtained in 75% yield (Scheme 3).
tries 1e7) only the ortho adduct was obtained. With pyridine-3- A plausible explanation for the regioselective formation of the
carbaldehyde and 2,4,5-trimethoxybenzaldehyde (entries 8 and ortho adducts is illustrated in the Scheme 4. InCl3 as Lewis acid
9) the para adducts 5h and 5i were also formed, while when the plays a role in increasing the electrophilic character of the starting
reaction was performed with 3,4-methylenedioxybenzaldehyde aldehyde and stabilizing the o-QM intermediate. The coordination
(entry 10) compounds 4j and 7j were obtained in a 4.4:1.0 ratio of the oxygens lone electron pairs with In(III), presumably forms
(Fig. 3). a six-coordinate complex17 with an additional molecule of water
formed in the Knoevenagel condensation. Subsequent Michael

n et al. / Tetrahedron 70 (2014) 8480e8487
I. Hueso-Falco 8483

O
O para-quinonic adducts or 14-aryl-14H-dibenzo[a,i]xanthenes-8,13-
O
O dione as they reported.18 With respect to the other reference (Ref.
O
19) since the 1H NMR data were given using DMSO-d6 as solvent, we
O ran the spectra for our ortho-quinonic adduct obtained from 4-
O R
O O bromo-benzaldehyde (4c) and we obtained identical values to
those published as para-quinonic adduct. Furthermore, with the aim
5h R=3-pyridyl 7j
5i R=2,4,5-trimethoxyphenyl O to check this fact we synthesized one of the reported ‘para-quinone’
adduct following the procedure described by Bazgir et al.19 from
benzaldehyde, and we obtained the same compound that using
Fig. 3. Structures of compounds 5h, 5i, and 7j. InCl3, consequently the structures given in Ref. 19 are also wrong.

O O O
OH O Br
H MeO OH InCl3 (30 mol %), 3h
+ +
Br neat, 120ºC, 75%
O O OMe

Scheme 3. Formation of compound 8 from 7-methoxy-naphthalen-2-ol.

Cl Cl
Cl H O Cl
H O
In In
O O Cl O Cl

OH O HO O
O
InCl3
+
R
R H

O O R O
HO
A
B

Cl
H O Cl
In
O O Cl
O O

R R

O - H2 O O
- InCl3 HO

Scheme 4. Plausible formation of ortho-quinonic adducts in the presence of InCl3.

addition of 2-naphthol to the o-QM A provides the intermediate B The ortho-quinonic adducts (4ae4j, 7j, 8), the para-quinonic
that evolutes via intramolecular cyclization and dehydration to adducts (5h, 5i), and the dimer (6) were evaluated for anti-
yield the corresponding ortho adduct. Probably in the cases of proliferative activity against two tumoral cell lines, HEL and MCF7.
pyridine-3-carbaldehyde and 3,4-methylenedioxybenzaldehyde, Neither dimer (6) nor para-quinonic adducts were cytotoxic. Most
the formation of the mentioned In(III) complex is less effective due of the ortho-quinonic adducts were cytotoxic (Table 3). Conse-
to the presence of nitrogen or oxygen atoms, which tend also to quently, only the ortho-quinonic moiety resulted active. The best
interact with InCl3, and consequently the formation of the para-
Table 3
quinonic adducts 5h and 5i is detected (Table 2, entries 8 and 9). To
Antiproliferative activitya of ortho-quinonic adducts (4ae4j, 7j, 8) against HEL (hu-
the best of our knowledge, this multicomponent reaction mediated man erythroleukemia) and MCF7 (human breast cancer MCF-7) cell lines
by InCl3 leading to novel naphthopyrano-ortho-quinones has not
Compounds HEL MCF7
been previously reported.
Since that the para-quinonic adducts 5h and 5i were also formed 4a 1.20.7 8.51.9
4b >10 >10
in entries 8 and 9, we searched in the SciFinder for similar structures 4c 4.02.0 >10
and we found two references related to these structures.18,19 When 4d 1.60.7 1.91.0
we compared our NMR data with those, we found some differences, 4e 7.52.5 >10
especially in the shift of the signal for the only non-aromatic proton 4f 3.81.9 >10
4g >10 >10
and carbon in the pyran ring. On the other hand, the published NMR
4h 4.62.7 >10
data were very close to those of our ortho-quinonic adducts. In fact 4i 1.80.9 4.12.0
when we directly compared the 1H NMR and 13C NMR spectrum of 4j 0.70.4 3.92.4
our ortho-quinonic adducts with the para-quinonic adducts in- 7j 1.80.9 4.12.8
cluded in the Supplementary data of Ref. 18, they were identical, 8 1.70.7 3.01.9
Flavopyridol 0.20.1 0.20.2
inclusive for the adduct 4b whose X-ray was obtained Adriamicine 0.10.0 1.10.1
(Supplementary data). Consequently Wu et al. using silica sup- a
Expressed as IC50 values given in mM determined as meansSD (n¼3).
ported perchloric acid obtained ortho-quinonic adducts instead of
8484
n et al. / Tetrahedron 70 (2014) 8480e8487
I. Hueso-Falco
values were achieved with adducts containing electron rich sub-
stituents (i.e., 4i and 4j), or halogens (i.e., 4a, 4d and 8). The adducts
with electron releasing substituent (4c), or with heteroaromatic
ring (4h) were less active, besides compound 4b without sub-
stituents in the aromatic ring was inactive.
3. Conclusion
In short we have developed an efficient protocol for the prep-
aration of dibenzo[a,h]anthracenes through a multicomponent re-
action from 2-hydroxy-1,4-naphthoquinone, b-naphthol, and
aromatic aldehydes in the presence of indium trichloride as catalyst
under solvent-free conditions. This domino reaction implies
Knoevenagel condensation, Michael addition, intramolecular cy-
clization, and dehydration. Based on the structural determination
of our quinonic adducts we found that some related structures
previously reported were wrong. The ortho-quinonic adducts were
cytotoxic against HEL and MCF7 cell lines and the type of sub-
stituent on the aromatic ring of the pyran moiety seems to mod-
ulate the antiproliferative activity.
4. Experimental
4.1. General methods
Unless otherwise indicated, all solvents and reagents were ob-
tained commercially and used without further purification. All re-
actions were monitored by TLC with silica gel-plates. NMR spectra
were obtained on a Bruker Avance 400 or Bruker AMX 500 spec-
trometers. The 1H NMR chemical shifts were measured relative to
CDCl3, DMSO-d6 with tetramethylsilane (TMS) as the internal ref-
erence (CDCl3: d¼7.26 ppm; DMSO-d6: d¼2.50 ppm; TMS:
d¼0.00 ppm). The 13C NMR chemical shifts were given using CDCl3
or DMSO-d6 as the internal standard (CDCl3: d¼77.16 ppm; DMSO-
d6: d¼39.52 ppm). HREIMS were recorded using a high-resolution
magnetic trisector (EBE) mass analyzer. All compounds were
named using ACD40 Name-Pro program, which is based on IUPAC
rules.
4.2. General procedure for the multicomponent reaction be-
tween 2-hydroxy-1,4-naphthaquinone (1), aromatic aldehyde,
and 2-naphthol (2), with indium trichloride as catalyst
The aromatic aldehyde (1.0 mmol), 2-hydroxy-1,4-naphtho-
quinone (1) (1.1 mmol), and 2-naphthol (2) (1.0 mmol) were grin-
ded in a mortar for 5 min. Then, InCl3 (30 mol %) was added and the
reaction mixture was grinded again for 15 min, placed in a sealed
tube and kept in an oven at 120  C for 3 h. The resulting crude was
purified by chromatography.
4.3. Characterization of the multicomponent reaction
products
4.3.1. 14-(4-Bromophenyl)-14H-7-oxa-dibenzo[a,h]anthracene-
12,13-dione (4a). Following the general procedure described above,
63.9 mg of 2-hydroxy-1,4-naphthoquinone (0.356 mmol), 47.2 mg
of 2-naphthol (0.326 mmol), and 60.6 mg of 4-bromobenzaldehyde
(0.326 mmol) were grinded for 5 min, then 22.5 mg (30 mol %) of
InCl3 was added and the reaction mixture was grinded again for
15 min. After 3 h at 120  C, the resulting crude was purified by
preparative-TLC using DCM as eluant, to provide 112.1 mg (73%) of
4a, as an amorphous orange solid. Mp 281.9e283.9  C; 1H NMR
(500 MHz, CDCl3) d 8.14 (1H, d, J¼7.7 Hz, H-8), 8.11 (1H, dd, J¼7.7
and 1.0 Hz, H-11), 7.89 (2H, d, J¼8.8 Hz, H-1, H-5), 7.84 (1H, dd,
J¼8.8 and 1.3 Hz, H-4), 7.77 (1H, td, J¼7.7 and 1.0 Hz, H-9), 7.58 (1H,
td, J¼7.7 and 1.0 Hz, H-10), 7.54 (1H, d, J¼8.8 Hz, H-6), 7.46 (2H, m,
H-2, H-3), 7.29 (4H, m, H-20 , H-30 , H-50 , H-60 ), 5.86 (1H, s, H-
14) ppm; 13C NMR (100 MHz, CDCl3) d 178.4 (C, C-12 or C-13), 178.3
(C, C-12 or C-13), 157.5 (C, C-7a), 147.4 (C, C-6a), 142.3 (C, C-10 ), 135.3
(CH, C-9), 132.1 (C, C-4a), 131.9 (CH, C-30 and C-50 ), 131.6 (CH, C-10),
131.0 (C, C-14b), 130.9 (C, C-7b), 130.5 (CH, C-20 and C-60 ), 130.2 (C,
C-11a), 130.0 (CH, C-5), 129.6 (CH, C-11), 128.8 (CH, C-4), 127.8 (CH,
C-2), 125.9 (CH, C-3), 124.8 (CH, C-8), 123.8 (CH, C-1), 121.0 (C, C-40 ),
117.0 (CH, C-6), 116.4 (C, C-13a or C-14a), 116.1 (C, C-13a or C-14a),
34.9 (CH, C-14) ppm; HRESMS (þ): 489.0103 (calcd for
þ
C27H15O793 BrNa [Mþ23(Na)] 489.0102) and 491.0061 (calcd for
þ
81
C27H15O3 BrNa [Mþ23(Na)] 491.0082); IR nmax: 3048, 3004, 2918,
2854, 1700, 1664, 1633, 1587, 1513, 1483, 1456, 1434, 1363, 1281,
1231, 1209, 1178, 1154, 1090, 1069, 1010, 902, 835, 811, 776, 727, 655,
616, 556 cm1. Crystal data: orthorhombic, space group, Pbca, Z¼8,
a¼20.481(5), b¼9.392(2), c¼21.027(4)  A, V¼4044.7(4)  A3, m(Cu
1 3
Ka)¼3.0 mm , rcalcd¼1.53 g cm , S¼1.04, final R indices:
R1¼0.0557 and Rw¼0.1391 for 2427 observed from 3992 in-
dependent and 10,662 measured reflections (qmax¼74.1, I>2s(I)
criterion and 280 parameters), maximum and minimum residues
are 0.64 and 0.63 e  A3, respectively. The deposition number
CCDC 972177 has been assigned at the Cambridge Crystallographic
Data Centre.
4.3.2. 14-Benzo-14H-7-oxa-dibenzo[a,h]anthraceno-12,13-dione
(4b). Following the general procedure described above, 62.3 mg
(0.346 mmol) of 2-hydroxy-1,4-naphthoquinone, 46.3 mg of 2-
naphthol (0.312 mmol), and benzaldehyde (32 ml, 0.312 mmol)
were grinded for 5 min, then 22.2 mg (31 mol %) of InCl3 was added
and the reaction mixture was grinded again for 15 min. After
heating, the crude was purified by preparative-TLC using DCM, to
provide 84.9 mg (70%) of compound 4b. Mp 302.0e303.8  C; 1H
NMR (500 MHz, CDCl3) d 8.16 (1H, d, J¼7.6 Hz, H-8), 8.11 (1H, d,
J¼7.6 Hz, H-11), 7.99 (1H, d, J¼7.8 Hz, H-1), 7.88 (1H, d, J¼8.9 Hz, H-
5), 7.84 (1H, d, J¼7.8 Hz, H-4), 7.77 (1H, td, J¼7.6 and 1.2 Hz, H-9),
7.57 (2H, m, H-6, H-10), 7.46 (2H, m, H-2, H-3), 7.40 (2H, dd, J¼7.5
and 1.2 Hz, H-20 , H-60 ), 7.19 (2H, t, J¼7.5 Hz, H-30 , H-50 ), 7.09 (1H, t,
J¼7.5 Hz, H-40 ), 5.94 (1H, s, H-14) ppm; 13C NMR (100 MHz, CDCl3)
d 178.5 (C, C-13), 178.5 (C, C-12), 157.5 (C, C-7a), 147.5 (C, C-6a), 143.3
(C, C-10 ), 135.3 (CH, C-9), 132.1 (C, C-4a), 131.4 (CH, C-10), 131.2 (C, C-
14b), 131.1 (C, C-7b), 130.3 (C, C-11a), 129.7 (CH, C-5), 129.6 (CH, C-
11), 128.7 (CH, C-4, C-20 , C-30 , C-50 and C-60 ), 127.6 (CH, C-2), 127.0
(CH, C-40 ), 125.7 (CH, C-3), 124.7 (CH, C-8), 124.0 (CH, C-1), 117.1 (C,
C-13a or C-14a), 117.0 (CH, C-6), 116.8 (C, C-13a or C-14a), 35.4 (CH,
C-14) ppm; EIMS m/z (%): 388 ([M]þ, 36); 360 (11); 331 (26); 312
(14); 311 (55); 284 (22); 283 (100); 226 (21); HREIMS: 388.1112
(calcd for C27H16O3 [M]þ 388.1099); IR nmax: 3060, 2921, 1723, 1699,
1655, 1633, 1589, 1513, 1455, 1368, 1284, 1235, 1179, 1076, 1018, 902,
811, 749, 704, 609 cm1. Crystal data for 4b: C27H16O3, ortho-
rhombic, space group P212121, a¼10.469.2(2), b¼10.515(3),
c¼16.831(5)  A, V¼1852.8(8)  A3, Z¼4, m(Mo Ka)¼0.09 mm1,
rcalcd¼1.39 g cm3, S¼0.94, final R indices: R1¼0.0661 and
Rw¼0.1265 for 752 observed from 1689 independent and 3841
measured reflections (qmax¼26.5 , I>2s(I) criterion and 272 pa-
rameters); maximum and minimum residues are 0.14 and
0.14 e  A3, respectively. The deposition number CCDC 972179 has
been assigned at the Cambridge Crystallographic Data Centre.
4.3.3. 14-(4-Nitrophenyl)-14H-7-oxa-dibenzo[a,h]anthracene-12,13-
dione (4c). Following the general procedure described above,
71.2 mg of 2-hydroxy-1,4-naphthoquinone (0.40 mmol), 53.0 mg of
2-naphthol (0.36 mmol), and 55.0 mg of 4-nitrobenzaldehyde
(0.36 mmol) were grinded for 5 min, then 25.8 mg (0.12 mmol)
of InCl3 was added and the reaction mixture was grinded again for
15 min. After heating, the resulting crude was purified by
preparative-TLC using DCM as eluant, to provide 103.1 mg (66%) of
compound 4c. 1H NMR (500 MHz, CDCl3) d 8.19 (1H, d, J¼7.7 Hz, H-

n et al. / Tetrahedron 70 (2014) 8480e8487
I. Hueso-Falco
8), 8.14 (1H, dd, J¼7.7 and 1.0 Hz, H-11), 8.05 (2H, d, J¼8.7 Hz, H-30 ,
H-50 ), 7.94 (1H, d, J¼8.8 Hz, H-5), 7.86 (2H, d, J¼8.8 Hz, H-1, H-4),
7.81 (1H, td, J¼7.7 and 1.0 Hz, H-9), 7.61 (4H, m, H-6, H-10, H-20 , H-
60 ), 7.49 (2H, m, H-2, H-3), 6.05 (1H, s, H-14) ppm; 13C NMR
(100 MHz, CDCl3) d 178.3 (C, C-13), 178.2 (C, C-12), 158.0 (C, C-7a),
150.2 (C, C-10 ), 147.4 (C, C-6a), 146.8 (C, C-40 ), 135.5 (CH, C-9), 132.2
(C, C-4a), 131.9 (CH, C-10), 130.8 (C, C-14b), 130.6 (C, C-7b), 130.5
(CH, C-5), 130.2 (C, C-11a), 129.8 (CH, C-11), 129.8 (CH, C-20 and C-
60 ), 129.0 (CH, C-4), 128.0 (CH, C-2), 126.1 (CH, C-3), 125.0 (CH, C-8),
124.1 (CH, C-30 , C-50 ), 123.4 (CH, C-1), 117.0 (CH, C-6), 115.5 (C, C-
13a), 115.2 (C, C-14a), 35.4 (CH, C-14) ppm; EIMS m/z (%): 433 ([M]þ,
28); 311 (38); 284 (22); 283 (100); 226 (13); 174 (10); 105 (10); 69
(17); HREIMS: 433.0938 (calcd for C27H15NO5 [M]þ 433.0950). IR
nmax 3081, 3052, 2916, 1696, 1630, 1570, 1508, 1342, 1272, 1229,
1203, 1172, 1150, 1108, 1087, 1015, 899, 813, 773, 707, 653, 553 cm1.
4.3.4. 14-(4-Chlorophenyl)-14H-7-oxa-dibenzo[a,h]anthracene-
12,13-dione (4d). Following the general procedure described above,
68.8 mg of 2-hydroxy-1,4-naphthoquinone (0.385 mmol), 50.9 mg of
2-naphthol (0.350 mmol), and 50.7 mg of 4-chlorobenzaldehyde
(0.350 mmol) were grinded for 5 min. Then, 23.7 mg (30 mol %) of
InCl3 was added and the reaction mixture was grinded again for
15 min. The resulting crude was purified by preparative-TLC using
DCM, to provide 113.1 mg (74%) of 4d as an amorphous orange solid.
1
H NMR (500 MHz, CDCl3) d 8.14 (1H, d, J¼7.6 Hz, H-8), 8.10 (1H, dd,
J¼7.6 and 1.0 Hz, H-11), 7.88 (2H, d, J¼8.9 Hz, H-1, H-5), 7.84 (1H, dd,
J¼8.9 and 1.5 Hz, H-4), 7.77 (1H, td, J¼7.7 and 1.0 Hz, H-9), 7.57 (1H,
td, J¼7.6 and 1.0 Hz, H-10), 7.53 (1H, d, J¼8.9 Hz, H-6), 7.45 (2H, m, H-
2, H-3), 7.32 (2H, dt, J¼8.6 and 2.0 Hz, H-20 , H-60 ), 7.15 (2H, dt, J¼8.6
and 2.0 Hz, H-30 , H-50 ), 5.87 (1H, s, H-14); 13C NMR (100 MHz, CDCl3)
d 178.5 (C, C-12 or C-13), 178.4 (C, C-12 or C-13), 157.5 (C, C-7a), 147.5
(C, C-6a), 141.8 (C, C-10 ),135.3 (CH, C-9), 132.9 (C, C-40 ),132.1 (C, C-4a),
131.6 (CH, C-10), 131.0 (C, C-14b), 130.9 (C, C-7b), 130.2 (C, C-11a),
130.1 (CH, C-20 , C-60 ), 130.0 (CH, C-5), 129.7 (CH, C-11), 128.9 (CH, C-
30 , C-50 ), 128.8 (CH, C-4), 127.8 (CH, C-2), 125.9 (CH, C-3), 124.8 (CH, C-
8), 123.8 (CH, C-1), 117.0 (CH, C-6), 116.5 (C, C-13a or C-14a), 116.2 (C,
C-13a or C-14a), 34.8 (CH, C-14); EIMS m/z (%): 422 ([M]þ, 41); 394
(11); 365 (24); 331 (11); 312 (12); 311 (49); 284 (21); 283 (100); 226
(14); 165 (11); 69 (16); HREIMS: 422.0708 (calcd for C27H15O3Cl [M]þ
422.0710); IR nmax: 3091, 3048, 3005, 2911, 2854, 1701, 1664, 1634,
1588, 1514, 1486, 1457, 1434, 1364, 1280, 1233, 1210, 1177, 1154, 1088,
1017, 903, 835, 811, 775, 733, 655, 616, 555 cm1.
4.3.5. 14-(4-Fluorophenyl)-14H-7-oxa-dibenzo[a,h]anthracene-
12,13-dione (4e). Following the general procedure described above,
56.4 mg of 2-hydroxy-1,4-naphthoquinone (0.314 mmol), 41.2 mg of
2-naphthol (0.283 mmol), and 4-fluorobenzaldehyde (31 ml,
0.283 mmol) were grinded for 5 min, then 19.6 mg (30 mol %) of
InCl3 was added and the reaction mixture was grinded again for
additional 15 min. After 3 h at 120  C, the resulting crude was pu-
rified by preparative-TLC using DCM, to provide 48.0 mg (46%) of 4e,
as an amorphous red solid. 1H NMR (500 MHz, CDCl3) d 8.16 (1H, d,
J¼7.6 Hz, H-8), 8.12 (1H, d, J¼7.6 Hz, H-11), 7.93 (1H, d, J¼8.4 Hz, H-
1), 7.89 (1H, d, J¼8.9 Hz, H-5), 7.85 (1H, d, J¼8.4 Hz, H-4), 7.83 (1H, t,
J¼7.6 Hz, H-9), 7.59 (1H, t, J¼7.6 Hz, H-10), 7.55 (1H, d, J¼8.9 Hz, H-
6), 7.47 (2H, m, H-2, H-3), 7.36 (2H, dd, J¼8.7 and 5.4 Hz, H-20 , H-60 ),
6.87 (2H, t, J¼8.7 Hz, H-30 , H-50 ), 5.92 (1H, s, H-14) ppm; 13C NMR
(100 MHz, CDCl3) d 178.5 (C, C-12 or C-13), 178.5 (C, C-12 or C-13),
162.7 (CeF, J¼239.6 Hz, C-40 ), 157.4 (C, C-7a), 147.5 (C, C-6a), 139.1 (C,
C-10 ), 135.3 (CH, C-9), 132.1 (C, C-4a), 131.5 (CH, C-10), 131.1 (C, C-
14b), 131.0 (C, C-7b), 130.3 (CH, J¼8.2 Hz, C-20 , C-60 ), 130.3 (C, C-11a),
129.9 (CH, C-5), 129.6 (CH, C-11), 128.8 (CH, C-4), 127.7 (CH, C-2),
125.8 (CH, C-3), 124.8 (CH, C-8), 123.8 (CH, C-1), 117.0 (CH, C-6), 116.8
(C, C-14a), 116.5 (C, C-13a), 115.6 (CH, J¼21.4 Hz, C-30 , C-50 ), 34.7 (CH,
C-14) ppm; EIMS m/z (%): 406 ([M]þ, 59); 378 (15); 376 (13); 350
(15); 349 (47); 313 (11); 312 (15); 311 (62); 298 (11); 284 (23); 283
8485
(100); 270 (16); 226 (18); 174 (13); HREIMS: 406.1013 (calcd for
C27H15O3F [M]þ 406.1005); IR nmax: 3068, 2922, 2854, 1696, 1658,
1633, 1588, 1501, 1460, 1365, 1282, 1232, 1211, 1177, 1158, 1091, 1017,
902, 841, 815, 774, 752, 733, 656, 602, 553 cm1.
4.3.6. 14-(2-Fluorophenyl)-14H-7-oxa-dibenzo[a,h]anthracene-
12,13-dione (4f). Following the general procedure described above,
58.6 mg of 2-hydroxy-1,4-naphthoquinone (0.326 mmol), 2-
naphthol (42.8 mg, 0.295 mmol), and 2-fluorobenzaldehyde
(32 ml, 0.295 mmol) were grinded for 5 min, then 20.6 mg
(31 mol %) of InCl3 was added and the reaction mixture was grinded
again for 15 min. After 3 h at 120  C, the resulting crude was pu-
rified by preparative-TLC using DCM, to provide 80.3 mg (67%) of
compound 4f. 1H NMR (400 MHz, CDCl3) d 8.21 (1H, d, J¼7.6 Hz, H-
8), 8.13 (1H, d, J¼7.6 Hz, H-11), 8.12 (1H, d, J¼8.2 Hz, H-1), 7.83 (3H,
m, H-4, H-5 and H-9), 7.61 (1H, t, J¼7.6 Hz, H-10), 7.53 (2H, m, H-2,
H-6), 7.45 (1H, d, J¼6 Hz, H-60 ), 7.43 (1H, d, J¼8.0 Hz, H-3), 7.07 (1H,
m, H-40 ), 6.98 (1H, m, H-50 ), 6.92 (1H, m, H-30 ), 6.08 (1H, s, H-
14) ppm; 13C NMR (100 MHz, CDCl3) d 178.4 (C, C-12 or C-13), 178.3
(C, C-12 or C-13), 160.5 (CeF, J¼247.2 Hz, C-20 ), 157.9 (C, C-7a), 147.3
(C, C-6a), 135.3 (CH, C-9), 132.0 (C, C-4a), 131.5 (CH, C-10), 131.5 (C,
C-14b), 131.3 (CH, J¼4.8 Hz, C-60 ), 131.0 (C, C-7b), 130.4 (C, C-11a),
130.2 (C, J¼12.5 Hz, C-10 ), 129.8 (CH, C-5), 129.6 (CH, C-11), 129.0
(CH, J¼6.8 Hz, C-40 ), 128.8 (CH, C-4), 127.7 (CH, C-2), 125.7 (CH, C-3),
124.8 (CH, C-8), 124.4 (CH, J¼2.5 Hz, C-50 ), 123.5 (CH, C-1), 117.0 (CH,
C-6), 116.1 (CH, J¼21.7 Hz, C-30 ), 116.0 (C, C-14a), 115.3 (C, C-13a),
30.3 (CH, C-14) ppm; EIMS m/z (%): 406 ([M]þ, 36); 378 (13); 349
(14); 311 (26); 284 (22); 283 (100); 226 (10); HREIMS: 406.0993
(calcd for C27H15O3F [M]þ 406.1005); IR nmax: 3065, 2928, 2858,
1728, 1699, 1666, 1637, 1592, 1490, 1460, 1371, 1289, 1241, 1216, 1178,
1096, 1073, 998, 909, 865, 846, 820, 756, 662, 629, 614 cm1.
4.3.7. 14-(Thiophen-2-yl)-14H-7-oxa-dibenzo[a,h]anthracene-12,13-
dione (4g). Following the general procedure described above,
57.8 mg (0.322 mmol) of 2-hydroxy-1,4-naphthoquinone, 42.9 mg
of 2-naphthol (0.294 mmol), and 2-thiophenecarboxaldehyde
(28 ml, 0.294 mmol) were grinded for 5 min, then 20.1 mg
(30 mol %) of InCl3 was added and the reaction mixture was grinded
again for 15 min. After heating, the crude was purified by
preparative-TLC using DCM, to provide 28.1 mg (25%) of compound
4g. 1H NMR (400 MHz, CDCl3) d 8.14 (2H, m, H-8, H-11), 8.04 (1H, d,
J¼8.5 Hz, H-1), 7.90 (1H, d, J¼9.0 Hz, H-5), 7.87 (1H, dd, J¼8.5 and
1.3 Hz, H-4), 7.77 (1H, td, J¼7.6 and 1.2 Hz, H-9), 7.59 (1H, td, J¼7.6
and 1.2 Hz, H-10), 7.53 (2H, m, H-2, H-6), 7.47 (1H, m, H-3), 7.03 (1H,
dd, J¼5.1 and 1.2 Hz, H-30 ), 6.93 (1H, d, J¼3.6 Hz, H-50 ), 6.26 (1H, dd,
J¼5.1 and 3.6 Hz, H-40 ), 6.26 (1H, s, H-14) ppm; 13C NMR (100 MHz,
CDCl3) d 178.5 (C, C-12), 178.4 (C, C-13), 157.5 (C, C-7a), 147.5 (C, C-
6a), 147.0 (C, C-10 ), 135.3 (CH, C-9), 132.0 (C, C-4a), 131.6 (CH, C-10),
131.3 (C, C-14b), 131.0 (C, C-7b), 130.2 (C, C-11a), 130.0 (CH, C-5),
129.7 (CH, C-11), 128.8 (CH, C-4), 127.8 (CH, C-2), 126.9 (CH, C-40 ),
126.1 (CH, C-50 ), 125.9 (CH, C-3), 124.9 (CH, C-8), 124.8 (CH, C-30 ),
123.8 (CH, C-1), 117.0 (CH, C-6), 116.6 (C, C-14a), 116.0 (C, C-13a),
30.0 (CH, C-14) ppm; EIMS m/z (%): 394 ([M]þ, 100); 393 (20); 366
(28); 338 (28); 337 (93); 333 (20); 311 (20); 283 (51); 226 (24); 183
(13); 131 (9); 69 (10); HREIMS: 394.0675 (calcd for C25H14O3S [M]þ
394.0664); IR nmax: 3058, 3025, 2921, 1693, 1647, 1629, 1585, 1571,
1536, 1485, 1453, 1362, 1279, 1233, 1207, 1166, 1088, 1008, 899, 821,
768, 754, 696, 619, 548 cm1.
4.3.8. 14-(Pyridin-3-yl)-14H-7-oxa-dibenzo[a,h]anthracene-12,13-
dione (4h) and 14-(pyridin-3-yl)-14H-7-oxa-benzo[a]naphthacene-
8,13-dione (5h). Following the general procedure described above,
66.4 mg of 2-hydroxy-1,4-naphthoquinone (0.370 mmol), 48.9 mg
of 2-naphthol (0.336 mmol), and 32 mL (0.334 mmol) of 3-
pyridincarboxaldehyde were grinded for 5 min, then 22.5 mg
(30 mol %) of InCl3 was added and the reaction mixture was grinded
8486
n et al. / Tetrahedron 70 (2014) 8480e8487
I. Hueso-Falco
again for 15 min. After 3 h at 120  C, the resulting crude was purified
by preparative-TLC using DCM to yield 69.2 mg (53%) of compound
4h as an amorphous red-orange solid and 7.1 mg (6%) of compound
5h as an amorphous dark brown solid. Compound 4h: 1H NMR
(500 MHz, CDCl3) d 8.60 (1H, d, J¼2.0 Hz, H-20 ), 8.33 (1H, dd, J¼4.8
and 2.0 Hz, H-50 ), 8.18 (1H, d, J¼7.6 Hz, H-8), 8.13 (1H, d, J¼7.6 Hz, H-
11), 7.90 (2H, m, H-1, H-5), 7.86 (1H, d, J¼7.8 Hz, H-4), 7.80 (2H, m, H-
9, H-60 ), 7.61 (1H, t, J¼7.6 Hz, H-10), 7.56 (1H, d, J¼8.9 Hz, H-6), 7.47
(2H, m, H-2, H-3), 7.14 (1H, dd, J¼8.0 and 4.8 Hz, H-40 ), 5.93 (1H, s, H-
14) ppm; 13C NMR (100 MHz, CDCl3) d 178.3 (C, C-12 or C-13), 178.3
(C, C-12 or C-13), 157.9 (C, C-7a), 150.0 (CH, C-20 ), 148.1 (CH, C-50 ),
147.6 (C, C-6a), 139.0 (C, C-10 ), 136.5 (C, C-60 ), 135.4 (CH, C-9), 132.2
(C, C-4a), 131.7 (CH, C-10), 130.8 (C, C-7b or C-14b), 130.7 (C, C-7b or
C-14b), 130.3 (C, C-11a), 130.3 (CH, C-5), 129.7 (CH, C-11), 128.9 (CH,
C-4), 127.9 (CH, C-2), 126.0 (CH, C-3), 124.9 (CH, C-8), 123.7 (CH, C-
40 ), 123.5 (CH, C-1), 117.0 (CH, C-6), 115.7 (C, C-14a), 115.7 (C, C-13a),
33.3 (CH, C-14) ppm; EIMS m/z (%): 389 ([M]þ, 35); 332 (10); 312
(14); 311 (60); 284 (23); 283 (100); 226 (18); 167 (6); HREIMS:
389.1046 (calcd for C26H15NO3 [M]þ 389.1052); IR nmax: 3059, 3028,
2921, 2851, 1779, 1703, 1667, 1632, 1590, 1514, 1462, 1424, 1352, 1285,
1236, 1091, 1077, 1022, 980, 963, 903, 814, 772, 732, 712, 622,
557 cm1. Compound 5h: 1H NMR (500 MHz, CDCl3) d 8.78 (1H, s, H-
20 ), 8.35 (1H, d, J¼4.1 Hz, H-40 ), 8.18 (1H, dd, J¼6.3 and 2.5 Hz, H-9),
8.10 (1H, dd, J¼6.3 and 2.5 Hz, H-12), 7.91 (1H, d, J¼8.0 Hz, H-1), 7.88
(1H, d, J¼9.0 Hz, H-5), 7.84 (1H, d, J¼8.0 Hz, H-4), 7.73 (2H, m, H-10
and H-11), 7.66 (1H, d, J¼8.0 Hz, H-60 ), 7.61 (1H, d, J¼9.0 Hz, H-6),
7.49 (1H, t, J¼8.0 Hz, H-2), 7.44 (1H, t, J¼8.0 Hz, H-3), 7.13 (1H, dd,
J¼8.0 and 4.1 Hz, H-50 ), 6.08 (1H, s, H-14) ppm; 13C NMR (100 MHz,
CDCl3) d 183.5 (C, C-13), 178.6 (C, C-8), 150.4 (C, C-7a), 150.3 (CH, C-
20 ), 148.4 (CH, C-40 ), 147.9 (C, C-6a), 138.9 (C, C-10 ), 136.4 (C, C-60 ),
134.6 (CH, C-10 or C-11), 133.9 (CH, C-10 or C-11), 132.1 (C, C-12a),
132.0 (C, C-4a), 131.0 (C, C-8a), 130.8 (C, C-14b), 130.3 (CH, C-5), 129.0
(CH, C-4), 127.8 (CH, C-2), 126.8 (CH, C-9), 126.7 (CH, C-12), 125.8
(CH, C-3), 123.9 (CH, C-50 ), 123.3 (CH, C-1), 122.4 (C, C-13a), 117.6 (CH,
C-6), 114.8 (C, C-14a), 33.6 (CH, C-14) ppm; EIMS m/z (%): 389 ([M]þ,
54); 312 (23); 311 (100); 283 (6); 226 (10); HREIMS: 389.1058 (calcd
for C26H15NO3 [M]þ 389.1052); IR nmax: 3062, 2924, 2853, 1681, 1650,
1595, 1515, 1463, 1424, 1366, 1334, 1302, 1269, 1230, 1071, 1024, 989,
925, 813, 725, 623 cm1.
4.3.9. 14-(2,4,5-Trimethoxyphenyl)-14H-7-oxa-dibenzo[a,h]anthra-
cene-12,13-dione (4i) and 14-(2,4,5-trimethoxyphenyl)-14H-7-oxa-
benzo[a]naphthacene-8,13-dione (5i). Following the general pro-
cedure described above, 48.3 mg (0.269 mmol) of 2-hydroxy-1,4-
naphthoquinone, 35.5 mg of 2-naphthol (0.244 mmol), and
48.8 mg of 2,4,5-trimethoxybenzaldehyde (0.244 mmol) were
grinded for 5 min, then 18.0 mg (31 mol %) of InCl3 was added and
the reaction mixture was grinded again for 15 min. After heating, the
resulting crude was purified by preparative-TLC using DCM to yield
8.6 mg (7.4%) of compound 4i as an amorphous red solid and 7.5 mg
(6.4%) of compound 5i as an amorphous dark orange solid. Com-
pound 4i: 1H NMR (400 MHz, CDCl3) d 8.24 (1H, d, J¼8.5 Hz, H-1),
8.18 (1H, d, J¼7.6 Hz, H-8), 8.12 (1H, d, J¼7.6 Hz, H-11), 7.79 (3H, m,
H-4, H-5, H-9), 7.58 (1H, t, J¼7.6 Hz, H-10), 7.49 (2H, m, H-2, H-6),
7.41 (1H, t, J¼8.5 Hz, H-3), 6.92 (1H, s, H-60 ), 6.41 (1H, s, H-30 ), 6.03
(1H, s, H-14), 3.81 (3H, s, H-100 ), 3.76 (3H, s, H-200 or H-300 ), 3.75 (3H, s,
H-200 or H-300 ) ppm; 13C NMR (100 MHz, CDCl3) d 178.7 (C, C-12),
178.5 (C, C-13), 157.5 (C, C-7a), 151.7 (C, C-20 ), 149.2 (C, C-40 or C-50 ),
147.4 (C, C-6a), 143.6 (C, C-40 or C-50 ), 135.2 (CH, C-9), 131.9 (C, C-4a),
131.6 (CH, C-14b), 131.3 (C, C-7b), 131.2 (C, C-10), 130.3 (C, C-11a),
129.5 (CH, C-11), 129.1 (CH, C-5), 128.6 (CH, C-4), 127.4 (CH, C-2),
125.4 (CH, C-3), 124.6 (CH, C-8), 124.2 (CH, C-1), 123.7 (CH, C-10 ),
117.6 (C, C-14a), 116.8 (CH, C-6), 116.1 (C, C-13a), 115.0 (CH, C-60 ), 98.8
(CH, C-30 ), 57.4 (CH3, C-100 ), 57.0 (CH3, C-200 or C-300 ), 56.1 (CH3, C-200
or C-300 ), 30.7 (CH, C-14) ppm; EIMS m/z (%): 478 ([M]þ, 100); 448
(31); 447 (98); 419 (10); 39 (129); 313 (14); 312 (47); 311 (35); 283
(43); 226 (12); HREIMS: 478.1410 (calcd for C30H22O6 [M]þ
478.1416). IR nmax: 3060, 2935, 2848, 1699, 1664, 1637, 1591, 1461,
1369, 1286, 1237, 1210, 1180, 1093, 1031, 907, 863, 816, 773, 736, 658,
553 cm1. Compound 5i: 1H NMR (500 MHz, CDCl3) d 8.27 (1H, d,
J¼8.0 Hz, H-1), 8.18 (1H, m, H-9), 8.06 (1H, m, H-12), 7.79 (1H, d,
J¼8.0 Hz, H-4), 7.78 (1H, J¼8.9 Hz, H-5), 7.71 (2H, m H-10, H-11), 7.54
(1H, d, J¼8.9 Hz, H-6), 7.49 (1H, t, J¼8.0 Hz, H-2), 7.41 (1H, t, J¼8.0 Hz,
H-3), 6.88 (1H, s, H-60 ), 6.43 (1H, s, H-30 ), 6.21 (1H, s, H-14), 3.90 (3H,
s, H-100 ), 3.76 (3H, s, H-200 ), 3.74 (3H, s, H-300 ) ppm; 13C NMR
(100 MHz, CDCl3) d 183.7 (C, C-13), 179.2 (C, C-8), 151.3 (C, C-20 ),
150.7 (C, C-7a), 149.3 (C, C-40 ), 147.7 (C, C-6a), 143.6 (C, C-50 ), 134.4
(CH, C-11), 133.5 (C, C-10), 132.2 (CH, C-12a), 131.8 (C, C-4a), 131.5 (C,
C-14b), 131.0 (C, C-8a), 129.2 (CH, C-5), 128.7 (CH, C-4), 127.2 (CH, C-
2), 126.7 (CH, C-9, C-12), 125.3 (CH, C-3), 123.9 (CH, C-1), 123.4 (CH,
C-10 ), 123.0 (C, C-13a), 117.5 (CH, C-6), 116.7 (C, C-14a), 114.6 (CH, C-
60 ), 98.3 (CH, C-30 ), 57.1 (CH3, C-100 ), 56.8 (CH3, C-200 ), 56.1 (CH3, C-
300 ), 30.7 (CH, C-14) ppm; EIMS m/z (%): 478 ([M]þ, 100); 448 (7); 447
(26); 312 (11); 311 (51); 226 (6); 144 (16); HREIMS: 478.1407 (calcd
for C30H22O6 [M]þ 478.1416); IR nmax: 3061, 2930, 2851, 1679, 1647,
1595, 1514, 1463, 1366, 1334, 1307, 1269, 1231, 1207, 1116, 1069, 1032,
989, 927, 816, 750, 721, 600, 553 cm1.
4.3.10. 14-Benzo[1,3]dioxol-5-yl-14H-7-oxa-dibenzo[a,h]anthracene-
12,13-dione (4j) and 7-benzo[1,3]dioxol-5yl-7H-14-oxo-benzo[a]
naphthacene-5,6,8,13-tetraone (7j). Following the general pro-
cedure described above, 69.7 mg of 2-hydroxy-1,4-naphthoquinone
(0.388 mmol), 51.4 mg of 2-naphthol (0.353 mmol), and 53.8 mg of
3,4-methylenedioxybenzaldehyde (0.358 mmol) were grinded,
then 24.2 mg (30 mol %) of InCl3 was added and the reaction
mixture was grinded again for 15 min. After heating, the resulting
crude was purified by preparative-TLC using DCM to yield 50.9 mg
(33%) of compound 4j as an amorphous red solid and 12.4 mg (8%)
of compound 7j as an amorphous dark red solid. Compound 4j: 1H
NMR (400 MHz, CDCl3) d 8.12 (1H, d, J¼7.7 Hz, H-8), 8.09 (1H, d,
J¼7.7 Hz, H-11), 7.97 (1H, d, J¼8.0 Hz, H-1), 7.86 (1H, d, J¼9.0 Hz, H-
5), 7.83 (1H, d, J¼8.0 Hz, H-4), 7.75 (1H, td, J¼7.7 and 1.1 Hz, H-9),
7.56 (1H, t, J¼7.7 Hz, H-10), 7.49 (2H, m, H-2, H-6), 7.44 (1H, td,
J¼8.0 and 1.1 Hz, H-3), 6.90 (1H, dd, J¼8.0 and 1.6 Hz, H-60 ), 6.82
(1H, d, J¼1.6 Hz, H-20 ), 6.62 (1H, d, J¼8.0 Hz, H-50 ), 5.82 (2H, s, H-
200 ), 5.79 (1H, s, H-14) ppm; 13C NMR (100 MHz, CDCl3) d 178.5 (C, C-
12 and C-13), 157.1 (C, C-7a), 147.9 (C, C-10 ), 147.3 (C, C-6a), 146.5 (C,
C-40 ), 137.3 (C, C-30 ), 135.3 (CH, C-9), 132.0 (C, C-4a), 131.4 (CH, C-10),
131.1 (C, C-14b), 131.0 (C, C-7b), 130.2 (C, C-11a), 129.7 (CH, C-5),
129.5 (CH, C-11), 128.7 (CH, C-4), 127.6 (CH, C-2), 125.7 (CH, C-3),
124.7 (CH, C-8), 123.9 (CH, C-1), 122.2 (CH, C-60 ), 117.0 (C, C-14a),
117.0 (CH, C-6), 116.7 (C, C-13a), 109.2 (CH, C-20 ), 108.3 (CH, C-50 ),
101.1 (CH2, C-200 ), 34.9 (CH, C-14) ppm; EIMS m/z (%): 432 ([M]þ,
100); 376 (16); 375 (50); 312 (12); 311 (45); 284 (13); 283 (55); 226
(12); 202 (8); 159 (8); 69 (20); HREIMS: 432.0990 (calcd for
C28H16O5 [M]þ 432.0998); IR nmax: 3071, 2927, 2858, 1705, 1662,
1640, 1594, 1489, 1444, 1372, 1291, 1239, 1218, 1182, 1097, 1041, 928,
908, 863, 817, 777, 739, 663, 634, 553 cm1. Compound 7j: 1H NMR
(500 MHz, CDCl3) d 8.24 (1H, d, J¼7.7 Hz, H-1), 8.19 (1H, td, J¼4.7
and 2.0 Hz, H-12), 8.14 (1H, d, J¼7.7 Hz, H-4), 8.06 (1H, td, J¼4.7 and
2.0 Hz, H-9), 7.81 (1H, td, J¼7.7 and 1.0 Hz, H-2), 7.76 (2H, t,
J¼4.7 Hz, H-10, H-11), 7.63 (1H, t, J¼7.7 Hz, H-3), 6.96 (1H, d,
J¼1.8 Hz, H-20 ), 6.88 (1H, dd, J¼8.1 and 1.8 Hz. H-60 ), 6.67 (1H, d,
J¼8.1 Hz, H-50 ), 5.87 (2H, s, H-200 ), 5.26 (1H, s, H-7); 13C NMR
(100 MHz, CDCl3) d 182.7 (C, C-8), 178.2 (C, C-6), 177.6 (C, C-5 or C-
13), 177.5 (C, C-5 or C-13), 156.1 (C, C-14a), 148.5 (C, C-13a), 148.1 (C,
C-30 ), 147.4 (C, C-40 ), 135.7 (CH, C-2), 135.0 (C, C-10 ), 134.9 (CH, C-11),
134.2 (CH, C-10), 132.0 (CH, C-3), 131.8 (C, C-8a), 130.8 (C, C-12a),
130.1 (C, C-4a), 130.0 (CH, C-4), 129.9 (C, C-14b), 127.0 (CH, C-9),
126.8 (CH, C-12), 125.4 (CH, C-1), 124.9 (C, C-6a or C-7a), 122.4 (CH,
C-60 ), 116.3 (C, C-6a or C-7a), 109.3 (CH, C-20 ), 108.6 (CH, C-50 ), 101.3
(CH2, C-200 ), 33.0 (CH, C-7) ppm; EIMS m/z (%): 462 ([M]þ, 100); 445

n et al. / Tetrahedron 70 (2014) 8480e8487
I. Hueso-Falco
(18); 434 (30); 404 (22); 376 (13); 313 (20); 286 (15); 281 (15); 263
(10); 405 (22); 376 (13); 313 (20); 286 (15); 281 (15); 263 (10); 188
(15); 144 (26); 131 (10); 119 (10); 115 (10); 69 (24); HREIMS:
462.0733 (calcd for C28H14O7 [M]þ 462.0740). IR nmax: 3070, 2923,
2855, 1662, 1594, 1486, 1442, 1359, 1288, 1273, 1250, 1229, 1193,
1091, 1037, 947, 850, 812, 771, 733, 719, 611, 578 cm1.
4.3.11. 14-(4-Bromophenyl)-2-methoxy-14H-7-oxa-dibenzo[a,h]an-
thracene-12,13-dione (8). Following the general procedure de-
scribed above, 55.9 mg (0.311 mmol) of 2-hydroxy-1,4-
naphthoquinone, 49.9 mg of 7-methoxy-2-naphthol (0.281 mmol),
and 52.3 mg of 4-bromobenzaldehyde (0.280 mmol) were grinded
for 5 min, then 19.0 mg (30 mol %) of InCl3 was added and the re-
action mixture was grinded again for 15 min. After 3 h at 120  C, the
resulting crude was purified by preparative-TLC using DCM, to pro-
vide 104.4 mg of compound 8 (75%) as an orange solid. 1H NMR
(500 MHz, CDCl3) d 8.13 (1H, d, J¼7.5 Hz, H-8), 8.10 (1H, d, J¼7.5 Hz,
H-11), 7.77 (2H, m, H-5, H-9), 7.70 (1H, d, J¼8.8 Hz, H-4), 7.58 (1H, t,
J¼7.5 Hz, H-10), 7.36 (1H, d, J¼8.8 Hz, H-6), 7.30 (2H, d, J¼8.5 Hz, H-30 ,
H-50 ), 7.27 (2H, d, J¼8.5 Hz, H-20 , H-60 ), 7.09 (1H, s, H-1), 7.06 (1H, s,
H-1), 7.06 (1H, d, J¼8.8 Hz, H-3), 5.71 (1H, s, H-14), 3.80 (3H, s, H-
100 ) ppm; 13C NMR (100 MHz, CDCl3) d 178.4 (C, C-12 or C-13), 178.4
(C, C-12 or C-13), 159.1 (C, C-2), 157.4 (C, C-7a), 147.8 (C, C-6a), 142.3
(C, C-10 ), 135.3 (CH, C-9), 132.5 (C, C-14b), 131.8 (CH, C-30 and C-50 ),
131.5 (CH, C-10), 130.9 (C, C-7b), 130.6 (CH, C-20 and C-60 ), 130.3 (CH,
C-4), 130.2 (C, C-11a), 129.6 (CH, C-11), 129.6 (C, C-5), 127.3 (C, C-4a),
124.8 (CH, C-8), 121.0 (C, C-40 ), 118.2 (CH, C-3), 116.0 (C, C-13a), 115.3
(C, C-14a), 114.3 (CH, C-6), 102.8 (CH, C-1), 55.4 (CH3, C-100 ), 35.3 (CH,
C-14) ppm; EIMS m/z (%): 498 ([M]þ, 23); 496 ([M]þ, 22); 342 (12);
341 (44); 330 (11); 329 (23); 328 (100); 313 (39); 300 (42); 283 (13);
270 (16); 257 (46); 200 (15); 150 (10); 69 (19); HREIMS: 496.0318
þ
(calcd for C28H17O79 4 Br [M] 496.0310) and 498.0292 (calcd for
C28H17O481Br [M]þ 498.0290); IR nmax: 3066, 2920, 1710, 1669, 1633,
1592, 1521, 1490, 1460, 1370, 1286, 1241, 1214, 1174, 1137, 1092, 1072,
1009, 966, 907, 834, 773, 720, 660, 601 cm1.
4.4. MTT cell viability assay
The human cancer cell lines HL60 (promyelocytic leukemia) and
MCF-7 (breast adenocarcinoma) were purchased from ATCC and
cultured in RPMI or DMEN containing 10% FBS, respectively. The
MTT assay, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetra-
zolium bromide], was used to test cytotoxicity of adducts and cell
viability. Briefly, cells were plated in 96-well plates at 10,000 cells/
well. Twenty-four hours after plating, vehicle (0.1% DMSO, final
concentration) or compound was added to cells at indicated con-
centrations. Forty-eight hours following compound addition, MTT
(SigmaeAldrich, St. Louis, MO) was added to each well (0.5 mg/mL,
final concentration) and plates were incubated for an additional 3 h
at 37  C. Medium was then aspirated and the formazan product was
solubilized in SDSeHCl (20% SDS; HCl 0.02 M). The absorbance of
each well was measured at 570 nm using a microplate reader. Non-
linear regression analysis was performed to calculate IC50 according
to the GraphPad Prism 5 program (GraphPad Software, San Diego,
CA). The data are expressed by meanSD (n¼3).
4.5. Fukui indices calculations
A starting geometry was generated using the MMX method
implemented in PCmodel v 9.2.20 The optimal conformation was
subjected to full geometry optimization employing the density
functional theory (DFT) in gas phase using Jaguar 7.8 implemented
in the Schrodinger 9.2 package.21 The B3LYP functional with 6-31G**
basis set was utilized for optimizing the compounds along with the
computation of Fukui functions. Atomic Fukui indices were derived
from Mulliken population of the highest occupied molecular orbital
8487
(HOMO) and the LUMO, were used to quantify electrophilicity of
a molecule at a particular atomic site. The default convergence cri-
terion implemented in Jaguar was used for self-consistent field (SCF)
calculations (accuracy level¼quick, convergence criteria: maximum
iteration¼48, and energy change¼5105 hartree) and optimiza-
tion (maximum steps¼100, convergence criteria¼default, initial
Hessian¼Schlegel guess).22
Acknowledgements
We gratefully acknowledge the financial support from Spanish
MINECO SAF 2012-37344-C01 and SAF 2012-37344-C02. These
projects are also co-founded by the European Regional Development
Fund (ERDF). We also thank EU Research Potential (FP7-REGPOT-
2012-61367-IMBRAIN).
Supplementary data
Copies of 1H NMR and 13C NMR spectra of the dibenzo[a,h]an-
thracenes. Supplementary data associated with this article can be
found in the online version, at http://dx.doi.org/10.1016/
j.tet.2014.09.076.
References and notes
1. Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083e3185.
2. (a) Costantino, L.; Barlocco, D. Front. Med. Chem. 2010, 5, 381e391; (b) Klekota,
J.; Roth, F. Bioinformatics 2008, 24, 2518e2525; (c) Li, J.; Liu, K. C. Mini-Rev. Med.
Chem. 2004, 4, 207e233; (d) Li, J.; Liu, K.; Sakya, S. Mini-Rev. Med. Chem. 2005, 5,
1133e1144; (e) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W. D.;
Pippin, A. Comb. Chem. High Throughput Screen. 2004, 7, 473e491; (f) Cos-
tantino, L.; Barlocco, D. Curr. Med. Chem. 2006, 13, 65e85.
3. Wang, C.; Wan, Y.; Wang, H. Y.; Zhao, L. L.; Shi, J. J.; Zhang, X. X.; Wu, H. J.
Heterocycl. Chem. 2013, 50, 496e500.
4. Olyaei, A.; Vaziri, M.; Razeghi, R. Tetrahedron Lett. 2013, 54, 1963e1966.
5. Khurana, J. M.; Chaudhary, A.; Lumb, A.; Nand, B. Can. J. Chem. 2012, 90,
739e746.
6. (a) Jime
nez-Alonso, S.; Este
vez-Braun, A.; Za
rate, R.; Ravelo, A. G.; Lo
pez, M.
Tetrahedron 2007, 63, 3066e3074; (b) Jime
nez-Alonso, S.; Cha
vez-Orellana, H.;
Este
vez-Braun, A.; Ravelo, A. G.; Feresín, G.; Tapia, A. Tetrahedron 2008, 64,
8938e8942; (c) Jime
nez-Alonso, S.; Cha
vez-Orellana, H.; Este
vez-Braun, A.;
Ravelo, A. G.; Pe
rez-Sacau, E.; Machín, F. J. Med. Chem. 2008, 51, 6761e6772; (d)
Jime
nez-Alonso, S.; Pe
rez-Lomas, A. L.; Este
vez-Braun, A.; Mun ~ oz-Martínez, F.;
Ch
avez-Orellana, H.; Ravelo, A. G.; Gamarro, F.; Castanys, S.; Lo
pez, M. J. Med.
Chem. 2008, 51, 7132e7143; (e) Jime
nez-Alonso, S.; Guasch, J.; Este
vez-Braun,
A.; Ratera, I.; Veciana, J.; Ravelo, A. G. J. Org. Chem. 2011, 76, 1634e1643; (f)
Guedes, G.; Lo
pez-Rodríguez, M.; Ravelo, A. G.; Este
vez-Braun, A. Eur. J. Org.
Chem. 2012, 29, 5757e5766; (g) Pen ~ a, R.; Jime
nez-Alonso, S.; Feresin, G.; Tapia,
A.; Me


ndez-Alvarez, S.; Machín, F.; Ravelo, A. G.; Este
vez-Braun, A. J. Org. Chem.
2013, 78, 7977e7985.
7. (a) Willis, N. J.; Bray, C. D. Chem.dEur. J. 2012, 18, 9160e9173; (b) Quinone
Methides; Rokita, S. E., Ed.; Wiley: New York, NY, 2009; (c) Van der Water, R. W.;
Pettus, T. R. R. Tetrahedron 2002, 58, 5367e5405; (d) Pathak, T. P.; Sigman, M. S.
J. Org. Chem. 2011, 76, 9210e9215.
8. Parr, R. G.; Yang, W. J. Am. Chem. Soc. 1984, 106, 4049e4050.
9. Yang, W.; Mortier, W. J. J. Am. Chem. Soc. 1986, 108, 5708e5711.
10. Pe
rez-Sacau, E.; Díaz-Pen ~ ate, R. G.; Este
vez-Braun, A.; Ravelo, A. G.; García-
Castellano, J. M.; Pardo, L.; Campillo, M. J. Med. Chem. 2007, 50, 696e706.
11. Stefani, H. A.; Manarin, F.; Sousa, A. C. S.; Souza, F. B.; Frederico, B.; Ferraz, W. R.
Tetrahedron 2014, 70, 3243e3248.
12. Tanaka, K.; Aoki, H.; Hosomi, H.; Ohba, S. Org. Lett. 2000, 2, 2133e2134.
13. (a) Silveira, C. C.; Mendes, S.; Martins, G.; Guilherme, M.; Schlosser, S.; Kauf-
man, T. Tetrahedron 2013, 9076e9085; (b) Suryavanshi, P.; Sridharan, V.; Me-
nendez, J. C. Chem.dEur. J. 2013, 19, 13207e13215.
14. Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron 2009, 65, 7129e7134.
15. Liu, L.; Sarkisian, R.; Deng, Y.; Wang, H. J. Org. Chem. 2013, 78, 5751e5755.
16. (a) Martins, M. A. P.; Frizzo, P.; Morira, D. N.; Buriol, L.; Machado, P. Chem. Rev.
2009, 109, 4140e4182; (b) Rodríguez, B.; Bruckmann, A.; Rantanen, T.; Bolm, C.
Adv. Synth. Catal. 2007, 349, 2213e2233.
17. Pietrangelo, A.; Knight, S. C.; Gupta, A. K.; Yao, L. J.; Hillmyer, M. A.; Tolman, W.
B. J. Am. Chem. Soc. 2010, 132, 11649e11657.
18. Wu, L. Q.; Wu, Y. F.; Yang, C. G.; Yang, L. M.; Yang, L. J. J. Braz. Chem. Soc. 2010, 21,
941e945.
19. Dabiri, M.; Tisseh, Z. N.; Bazgir, A. J. Heterocycl. Chem. 2010, 47, 1062e1065.
20. PCMODEL 9.2. Serena Software: Bloomington, IN, Copyright 1988e2006. www.
serenasoft.com.
21. Jaguar, Version 7.8; Schrodinger: New York, NY, 2011.
22. Schlegel, B. Theor. Chim. Acta 1984, 66, 333e340.