Synthesis of fused chromene-1,4-naphthoquinones via ring-closing metathesis and Knoevenagel-electrocyclization under acid catalysis and microwave irradiation

Article abstract of DOI:10.1016/j.tet.2013.11.068

Two complementary methodologies involving olefin ring-closing metathesis and Knoevenagel-electrocyclization were utilized for the synthesis of α-xyloidones and fused chromene-1,4-naphthoquinones 5f-n and 6. The latter methodology was performed under acid

Full text of DOI:10.1016/j.tet.2013.11.068

Tetrahedron 70 (2014) 3266e3270
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Synthesis of fused chromene-1,4-naphthoquinones via ring-closing
metathesis and Knoevenagel-electrocyclization under acid catalysis
and microwave irradiation
David R. da Rocha a, Kelly Mota a, Illana M.C.B. da Silva a, Vitor F. Ferreira a,
,
Sabrina B. Ferreira b, Fernando de C. da Silva a
*
a
^
ꢀ
Universidade Federal Fluminense, Instituto de Química, Departamento de Química Organica, CEG, Campus do Valonguinho, 24020-141 Niteroi, Rio de
Janeiro, Brazil
b
~
Universidade Federal do Rio de Janeiro, Instituto de Química, Ilha do Fundao, Centro de Tecnologia, Bloco A, 21949-900 Rio de Janeiro, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 August 2013
Received in revised form 5 November 2013
Accepted 19 November 2013
Available online 23 November 2013
Two complementary methodologies involving olefin ring-closing metathesis and Knoevenagel-
electrocyclization were utilized for the synthesis of
naphthoquinones 5fen and 6. The latter methodology was performed under acid catalysis or micro-
wave irradiation allowing the synthesis of -xyloidones 5fej in moderate to good yield, which could not
a-xyloidones and fused chromene-1,4-
a
be obtained via the Knoevenagel-electrocyclization method. On the other hand, the lawsone bis-
alkylation (C and O) then RCM olefin enabled the preparation of simple xyloidone 5men and the ox-
epin-1,4-naphthoquinones 6.
Keywords:
Xyloidone
Pyranonaphthoquinone
Electrocyclization
Lawsone
Ó 2013 Elsevier Ltd. All rights reserved.
Metathesis reaction
1. Introduction
strains of Staphylococcus aureus15 and antimycotic activity against
fungal pathogens of plants.13
The 2H-chromene moiety is often found in natural products that
exhibit biological activity.1,2 The biological properties of this class
include apoptotic,3,4 anti-HIV,5,6 estrogen receptor modulating,7
antibacterial,8 tripanocidal,9 and leischmanicidal10 activities. An
important family are compounds containing chromenes coupled
with ortho- and para-quinones, and these have been isolated from
many types of plants, fungi, and insects.11 For example, 3,4-
dihydro-a-lapachone (1), and its isomer 3,4-dihydro-b-lapachone
(2) are the most important members of this class of chromenes.
Generally, these pyranonaphthoquinones are obtained in small
quantities from plant extracts along with lapachol (3) (Fig. 1).12
They are primarily isolated from the Central and South American
lapacho tree (Tabebuia avellanedae) as 1,2- and 1,4-naphthoquinone
moieties but can also be obtained from the stems of Catalpa ovate.13
The xyloidones present different types of biological activity such as
antibiotic activity against gram-negative bacteria of the genus
Brucella,14 strong antibacterial activity against multidrug resistant
Fig. 1. Natural 1,4- and 1,2-naphthoquinones.
The wide range of important biological activities of these mol-
ecules has stimulated further research into the synthesis of natural
and synthetic benzochromenes coupled with ortho- and para-qui-
none derivatives. Indeed, several synthetic approaches have been
reported for the preparation of these compounds. One of the first
reported syntheses of
Chiang, and they performed an oxidative 6
a
-xyloidone (1) was described by Dudley and
-electrocyclization of
p
isolapachol
with
2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in benzene to obtain a mixture of 1 and 2.16 Later, Ferreira
* Corresponding author. Tel.: þ55 21 26292229; e-mail address: gqofernando@
vm.uff.br (F.deC. da Silva).
and co-workers17 reported the Knoevenagel condensations of
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.11.068

D.R. da Rocha et al. / Tetrahedron 70 (2014) 3266e3270
3267
lawsone (4) under basic conditions with
to generate an ortho-quinone methide (o-QM), which yielded
xyloidone analogues 5aec in 33% yield after 6 -electrocyclization.
The same synthetic route and conditions were used by Oliveira and
co-workers for the preparation of the naturally occurring dihydro-
a
,
b
-unsaturated aldehydes
methide (o-QMs) intermediates; this was followed by 6
cyclization to yield the -xyloidone analogues.
p
-electro-
a
-
a
p
Initially, the reactions were performed using conventional
heating under reflux; a mixture of lawsone (4) and aldehyde in
a solution of EtOH/H2O was refluxed for 6e24 h to give chromenes
5fej. However, good results were only obtained in entry 1 (Table 1).
In the other examples tested, it was observed by TLC that the desired
a
-caryopterone (5d) and its isomer 6-hydroxy-dehydro-
a-lapa-
chone (5e, Scheme 1).18
Scheme 1. Synthesis of xyloidones 5aee from lawsone (4) via o-QM.
Lee and co-workers reinvestigated the electrocyclization re-
action of 4 for R1¼R2¼Me under basic and Lewis acid catalysis. The
best result was achieved with ethylenediamine diacetate 10 mol %
in refluxing benzene (80%).19,20 The same group used this meth-
odology for the synthesis of (ꢀ)-rhinacanthin, an important new
therapeutic target for the treatment of cancer.21 Muller and co-
product was formed but seems to degrade during the additional
time necessary for theses reactions. The reactions with cinna-
maldehyde and acrolein were unsuccessful, and the starting mate-
rials were recovered (entries 7 and 8). Reaction conditions with
a better heat distribution were necessary and could be achieved
with the use of a microwave irradiation. To avoid degradation, the
reactions were performed at 80 ꢁC, which increased the reaction
times for several reactions but resulted in good yields. Despite the
fact that the use of a microwave reactor increased the yields of the
reactions in most cases, this method was not very efficient for the
reactions with furfural, cinnamaldehyde and acrolein (entries 6e8).
workers also used this methodology for preparing
a-xyloidone
analogues in modest to good yield using b
-alanine as the base.22
Snieckus23 and co-workers used phenylboronic acid and glacial
acetic acid as the catalysts for the reaction with R1¼R2¼H to obtain
a
product with the chromene moiety fused with the 1,4-
naphthoquinone system in 50% yield after 1 h in refluxing toluene.
Since the lapachones are important minor components from
plants and they have important bioactive profile it is important to
produce them in large scale. Therefore, it is still necessary to de-
velop new robust methods or improve existing methods for the
synthesis of these substances. As part of our ongoing research
concerning the synthesis of bioactive naphthoquinones,24 we re-
port a simple and inexpensive improvement and a new approach to
the synthesis of fused chromene-1,4-naphthoquinones (5fen) from
Table 1
Synthesis of xyloidones by Knoevenagel-electrocyclization.
lawsone (4) and a,b-unsaturated aldehydes using acid catalysis or
microwave irradiation.24
Entry
Product
Reflux
MW
1
2
5f, R1¼R2¼Me, R3¼H
5g, R1¼Me; R2¼CH2eprenyl,
R3¼H
65% (24 h)
8% (72 h)
73% (1.5 h, 80 ꢁC)
70% (5.5 h, 80 ꢁC)
2. Results and discussion
3
4
5
6
7
5h, R1¼R2¼H, R3¼Me
5i, R1¼Me, R2¼R3¼H
5j, R1¼R3¼H, R2¼Pr
5k, R1¼R3¼H, R2¼furyl
5l, R1¼R3¼H, R2¼phenyl
26% (6 h)
14% (24 h)
6% (7 h)
Decompose
Reagent
recovered
Reagent
recovered
70% (1.2 h, 80 ꢁC)
54% (1 h, 80 ꢁC)
46% (1.5 h, 80 ꢁC)
Decompose
Reagent
recovered
Reagent
recovered
As previously mentioned, chromenes are substances of great
importance in chemistry, but there are few methods to synthesize
these compounds. When developing a new methodology to access
this class of compounds, some guiding principles were considered:
use of an inexpensive catalyst and green solvents. Thus, we utilized
formic acid for the Knoevenagel condensation between lawsone (4)
8
5m, R1¼R2¼R3¼H
and
a,b-unsaturated aldehydes to generate the ortho-quinone

3268
D.R. da Rocha et al. / Tetrahedron 70 (2014) 3266e3270
Given the difficulty of synthesizing other xyloidone derivatives,
including product 5m, we attempted another synthetic method
involving the O- and C-alkylation of lawsone (4) followed by
synthesis of several
crowave irradiation methods used to promote the Knoevenagel-
electrocyclization reaction between lawsone and the -un-
saturated aldehydes were complementary, and several and
xyloidones were obtained in moderate to good yields. The second
a- and b-xyloidones. The acid catalysis or mi-
a,b
cyclization using ring-closing metathesis (RCM), Scheme
2
a
b-
(entries 9e11).
Scheme 2. Synthetic xyloidone derivatives obtained using ring-closing metathesis.
For this purpose, the alkylation of the C-3 position of lawsone
methodology involving the O- and C-alkylation of lawsone followed
by cyclization using ring closing metathesis (RCM) with Grubbs’
(4) was initially considered. Thus, the synthesis of the intermediate
3-allyl-lawsone (8) was performed using the methodology of
Kongkathip and co-workers,25 in which a mixture of lawsone (4)
and allyl bromide was irradiated in a microwave vessel at 150 ꢁC
using N,N-dimethylformamide (DMF) as the solvent and potassium
carbonate as the base. In this reaction, the [3,3]-sigmatropic rear-
rangement of the initial O-alkylation product provided 3-allyl-
lawsone in 55% yield (Scheme 2). In contrast, the preparation of the
intermediate nor-lapachol (7) involved an adaptation of the
method described by Glazunov and research group,26 which is
a more modern and practical synthesis than that developed by
Fieser27 from lapachol. This methodology involves a Mannich re-
action of lawsone (4) methylamine and isobutyraldehyde followed
by elimination with p-toluenesulfonic acid in toluene under reflux
using a DeaneStark trap. Thus, it was possible to isolate nor-
lapachol as yellow crystals in 80% yield (Scheme 2). Subsequently,
we performed the O-alkylation using classical methods with an
alkyl bromide in dry acetone and potassium carbonate. The re-
actions with allyl and propargyl bromides generated the O-alkyl-
ation products in yields ranging from 40 to 66% (Scheme 2).
Finally, the bis-alkylated derivatives were heated in refluxing
dichloromethane in the presence of Grubbs’ catalyst (second gener-
ation), thus forming xyloidone derivatives 5m and 5n in good yields
and oxepin 6 (Scheme 2). Notably, this method enabled the synthesis
catalyst led to the formation of
oxepin in good yield. This latter method allowed the synthesis and
isolation of -xyloidone, which could not be obtained via the
a-xyloidone derivatives and one
a
Knoevenagel-electrocyclization method.
4. Experimental
4.1. General methods
The reagents were purchased from Aldrich or Acros Chemical
Co. Column chromatography was performed on silica gel 60 (Merck
70-230 mesh). Yields refer to purified compounds obtained by
chromatography and confirmed by spectroscopic data. Analytical
grade solvents were used. Melting points were obtained using
a Fischer Jones melting point device and are uncorrected. The re-
actions were monitored by thin-layer chromatography (TLC) on
0.25 mm E. Merck silica gel plates (60F-254) using UV light for
visualization. Infrared spectra were recorded on a PerkineElmer
FTIR Spectrum One spectrophotometer, calibrated relative to the
1601.8 cmꢂ1 absorbance of polystyrene. NMR spectra were recor-
ded on a Varian Unity Plus VXR (300 MHz) in CDCl3. The chemical
shift data are reported in units of
d parts per million (ppm)
downfield from tetramethylsilane or the solvent, which was used as
an internal standard; coupling constants (J) are reported in Hertz
and refer to the apparent peak multiplicities.
and isolation of a-xyloidone (5m), which hadbeen unsuccessfulusing
the Knoevenagel condensation reaction described above.
3. Conclusion
4.2. General experimental procedures
The two methodologies explored for the synthesis of fused
chromene-1,4-naphthoquinones resulted in the successful
4.2.1. General procedure for preparing 5fek under conventional
heating. To a round-bottom flask equipped with a magnetic stirring

D.R. da Rocha et al. / Tetrahedron 70 (2014) 3266e3270
3269
bar, lawsone (4,1 equiv), and 100 mL of a 1:1 ethanol/water mixture
(v/v), the aldehyde (1 equiv) and formic acid (1.5 equiv) were added
and mixed. The reaction mixture was heated at reflux for 1 h with
stirring. After total consumption of the starting material (verified
by TLC), the reaction mixture was cooled to room temperature and
concentrated under reduced pressure. Then, the resulting residue
was added to water, and this mixture was extracted with ethyl
acetate. The combined organic extracts were washed with water,
dried over anhydrous sodium sulfate, filtered, and concentrated
under reduced pressure. The crude product was purified by column
chromatography using silica gel and a gradient of hexane/EtOAc as
the eluent. The products were obtained in yields ranging from 6 to
65%. Microwave irradiation experiments were performed on
a model monowave 300 from Anton Paar using the 10 mL pressure
vial for closed vessel reactions, under the indicated power auto-
matically to reach and maintain the set temperature, specified in
each case, with ruby thermometer temperature for temperature
control and medium stirring speed using cylindrical stir bars
(10ꢃ6 mm).
6.66e6.68 (1H, m), 5.77e5.79 (1H, m), 5.24e5.28 (1H, m),
1.52e1.53 (3H, m) ppm; 13C NMR (DMSO-d6, 75 MHz): 21.6, 74.2,
116.6, 118.4, 126.1, 126.2, 127.1, 131.3, 131.4, 133.2, 134.0, 152.7, 179.6,
181.7 ppm.
4.2.3.5. 2-Propyl-2H-benzo[g]chromene-5,10-dione
(5j). Yield
(reflux/MW) 6/46%. Orange solid. Mp 67e69 ꢁC; IR (KBr, cmꢂ1):
n
2955, 2869,1672, 1650, 1570,1254, 1202, 969, 720; 1H NMR (DMSO-
d6, 300 MHz): 8.06e8.07 (2H, m), 7.65e7.71 (2H, m), 6.687e6.70
(1H, m), 5.78e5.81 (1H, m), 5.14e5.17 (1H, m), 1.72e1.90 (2H, m),
1.44e1.58 (2H, m), 0.94e0.97 (3H, m) ppm; 13C NMR (DMSO-d6,
75 MHz): 13.8, 17.4, 37.7, 77.7, 116.9, 118.6, 126.1, 126.2, 131.5, 133.2,
134.0, 153.0, 179.6, 181.7 ppm.
4.2.3.6. 2-Hydroxy-3-(2-methylprop-1-en-1-yl)naphthalene-1,4-
dione (7). To a solution of lawsone (4) (5 g, 28.7 mmol) in dry
toluene (300 mL) was added methylamine hydrochloride (2.3 g,
34 mmol), isobutyraldehyde (10.5 mL, 143.6 mmol) and p-tolue-
nesulfonic acid (6.47 g, 34 mmol). The reaction mixture was then
refluxed in a system equipped with a DeaneStark trap for 5 h. The
reaction mixture was then concentrated in vacuo, and the crude
solid was recrystallized from hexane (80%). Yellow solid; 1H NMR
4.2.2. General procedure for preparing 5fek under microwave
heating. A 10 mL microwave tube was loaded with 4 (11.5 mmol),
the corresponding aldehyde (11.5 mmol), formic acid (17.3 mmol),
and 5 mL of a 1:1 ethanol/water mixture (v/v), and the resulting
mixture was irradiated from 1 to 5.5 h. The internal temperature
reached 80 ꢁC. The solvent was evaporated under reduced pressure,
and the crude mixture was extracted with ethyl acetate (30 mL). The
organic layer was washed with water (3ꢃ20 mL), dried over anhy-
drous sodium sulfate, filtered, and concentrated under reduced
pressure. The residual solid product was purified by column chro-
matography using silica gel and a gradient of hexane/EtOAc as the
eluent. The products were obtained in yields ranging from 10 to 73%.
(CDCl3, 500 MHz):
d
1.68 (3H, d, J¼0.9 Hz), 1.99 (3H, d, J¼0.9 Hz),
6.01 (1H, sept, 0.9 Hz), 7.52 (1H, s), 7.69 (1H, dt, J¼1.8, 7.5 Hz), 7.76
(1H, dt, J¼1.8, 7.5 Hz), 8.10 (1H, dd, J¼1.8, 8.0 Hz), 8.13 (1H, dd, J¼1.8,
8.0 Hz); 13C NMR (CDCl3, 125 MHz): 21.6, 26.4, 113.5, 120.8, 125.9,
126.8, 129.4, 132.7, 132.8, 134.8, 143.4, 151.0, 181.4, 184.6.
4.2.3.7. 2-Allyl-3-hydroxy-1,4-naphthoquinone (8). A solution of
lawsone (4) (1.74 g, 10 mmol) in dimethylformamide (5 mL) was
added to potassium carbonate (1.4 g, 10 mmol) with stirring for
15 min at room temperature. Allyl bromide (3.0 g, 25 mmol) was
added dropwise at the same temperature. After the reaction mix-
ture was irradiated in a microwave for 10 min at 150 ꢁC in a sealed
vessel, the reaction mixture was cooled to room temperature and
filtered, and dichloromethane (30 mL) was added. The reaction
mixture was then washed with water (5ꢃ25 mL), dried over an-
hydrous sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified by flash column silica gel chromatography
eluting with a hexane/EtOAc gradient to afford the product 8 (55%).
4.2.3. Spectroscopic data for products 5fem and 6
4.2.3.1. 2,2-Dimethyl-2H-benzo[g]chromene-5,10-dione (
a-xyloi-
done, 5f). Yield (reflux/MW) 65/73%, Orange solid. Mp
145e146 ꢁC; IR (KBr, cmꢂ1):
n 2974, 2923, 1675, 1644, 1333, 1274,
1190, 1132, 967, 717; 1H NMR (DMSO-d6, 300 MHz): 8.08e8.11 (2H,
m), 7.67e7.71 (2H, m), 6.65 (1H, d, J¼10.0 Hz), 5.72 (1H, d,
J¼10.0 Hz), 1.66 (6H, s) ppm; 13C NMR (DMSO-d6, 75 MHz): 28.3,
80.4, 115.5, 117.8, 126.2, 130.8, 131.5, 131.6, 133.1, 133.9, 152.4, 179.8,
181.8 ppm.
Yellow solid; mp: 110e111 ꢁC. IR (KBr, cmꢂ1):
1589, 1372, 1350, 1272, 1230, 729; 1H NMR (CDCl3, 500 MHz):
3.29e3.31 (2H, m), 4.93e5.05 (2H, m), 5.80e5.88 (1H, m), 7.30
n 3356, 1660, 1644,
d
(1H, s), 7.60e7.72 (1H, m), 7.60e7.72 (1H, m), 8.00e8.07 (1H, m),
8.00e8.07 (1H, m); 13C NMR (CDCl3, 125 MHz): 27.3, 116.6, 121.7,
126.0, 126.7, 129.3, 132.7, 132.8, 133.6, 134.8, 153.0, 181.3, 184.0.
4.2.3.2. 2-Methyl-2-(4-methylpent-3-en-1-yl)-2H-benzo[g]chro-
mene-5,10-dione (5g). Yield (reflux/MW) 8/70%. Orange solid. Mp
96e98 ꢁC; IR (KBr, cmꢂ1):
n 3340, 2970, 2926,1675,1651,1337, 1272,
966, 720; 1H NMR (DMSO-d6, 300 MHz): 8.07e8.10 (2H, m),
7.67e7.71 (2H, m), 6.70 (1H, d, J¼10.0 Hz), 5.67 (1H, d, J¼10.0 Hz),
5.05e5.10 (1H, m), 1.90e2.00 (2H, m), 1.65e1.70 (2H, m), 1.62 (3H,
s), 1.54 (3H, s), 1.51 (3H, s) ppm; 13C NMR (DMSO-d6, 75 MHz): 17.6,
22.6, 25.5, 27.5, 41.5, 83.0, 115.9, 117.4, 123.3, 126.1, 129.7, 131.4,
132.2, 133.1, 133.8, 152.7, 179.6, 181.7 ppm.
4.2.4. General procedure of the O-alkylation. A solution of 7 or 8
(1 mmol) in dry acetone (5 mL) was added to potassium carbonate
(1.5 mmol) and stirred for 15 min at room temperature. Allyl or
propargyl bromide (1.5 mmol) was added dropwise at the same
temperature. After the reaction mixture was stirred for 3 h, the
reaction mixture was cooled to room temperature and filtered, and
dichloromethane (30 mL) was added. The reaction mixture was
then washed with water (5ꢃ25 mL), dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The residue was puri-
fied by flash column silica gel chromatography eluting with a hex-
ane/EtOAc gradient to afford the product.
4.2.3.3. 3-Methyl-2H-benzo[g]chromene-5,10-dione (5h). Yield
(reflux/MW) 26/70%. Red solid. Mp 189e191 ꢁC; IR (KBr, cmꢂ1):
n
2924, 1675, 1649, 1593, 1375, 1337, 1208, 720; 1H NMR (DMSO-d6,
300 MHz): 8.01e8.04 (2H, m), 7.63e7.67 (2H, m) 6.40 (1H, dd, J¼1.6,
1.6 Hz), 4.89 (1H, dd, J¼1.6, 1.3 Hz), 1.82 (3H, dd, J¼1.3, 1.3 Hz) ppm;
13C NMR (DMSO-d6, 75 MHz): 19.2, 70.4, 112.1, 119.5, 126.0, 126.1,
131.2, 131.3, 133.1, 133.2, 133.8, 151.3, 179.2, 181.8 ppm.
4.2.4.1. 2-(Allyloxy)-3-(2-methylprop-1-enyl)naphthalene-1,4-
dione (9). Yield: 66%; yellow oil. IR (KBr, cmꢂ1):
n
3079, 2915, 1668,
1651, 1596, 1574, 1447, 1379, 1328, 1295, 1265, 1200, 795, 728; 1H
NMR (CDCl3, 500 MHz): 1.62e1.63 (3H, m), 1.97e1.98 (3H, m),
4.2.3.4. 2-Methyl-2H-benzo[g]chromene-5,10-dione (5i). Yield
d
(reflux/MW) 14/54%. Orange solid. Mp 82e86 ꢁC; IR (KBr, cmꢂ1):
n
4.75e4.78 (2H, m), 5.20e5.25 (1H, m), 5.30e5.37 (1H, m),
5.91e6.04 (1H, m), 5.91e6.04 (1H, m), 7.66e7.72 (1H, m), 7.66e7.72
(1H, m), 8.03e8.08 (1H, m), 8.03e8.08 (1H, m); 13C NMR (CDCl3,
2974, 2924, 1674, 1647, 1632, 1336, 1303, 1259, 1199, 967, 719; 1H
NMR (DMSO-d6, 300 MHz): 8.04e8.06 (2H, m), 7.65e7.70 (2H, m),

3270
D.R. da Rocha et al. / Tetrahedron 70 (2014) 3266e3270
125 MHz): 21.4, 26.3, 73.4, 114.6, 118.2, 126.0, 126.2, 130.8, 131.4,
131.9, 133.1, 133.2, 133.6, 143.2, 155.3, 181.6, 185.3; HRESIMS m/z
269.1169 [MþH]þ (Calcd for C17H17O3þ: 269.1172).
6.13e6.17 (1H, m), 7.58e7.67 (1H, m), 7.58e7.67 (1H, m), 7.99e8.01
(1H, m), 7.99e8.01 (1H, m); 13C NMR (CDCl3, 125 MHz): 22.7, 66.8,
124.4, 126.1, 126.2, 126.9, 130.6, 131.6, 133.0, 133.6, 133.8, 158.þ3,
180.6, 184.6; HRESIMS m/z 227.0711 [MþH]þ (Calcd for C14H11O3
:
4.2.4.2. 2-(2-Methylprop-1-enyl)-3-(prop-2-ynyloxy)naphtha-
227.0703).
lene-1,4-dione (10). Yield: 45%; orange solid; mp: 80e81 ꢁC. IR
(KBr, cmꢂ1):
n
3261, 1663, 1649, 1594, 1562, 1332, 1310, 1264, 1199,
Acknowledgements
717; 1H NMR (CDCl3, 500 MHz):
d
1.58 (3H, s), 1.91e1.92 (3H, m),
1.96 (2H, d, J¼2.4 Hz), 2.42 (1H, t, J¼2.4), 5.95 (1H, m), 7.62e7.66
(1H, m), 7.62e7.66 (1H, m), 8.00e8.02 (1H, m), 8.00e8.02 (1H, m);
13C NMR (CDCl3, 125 MHz): 21.5, 26.4, 59.6, 76.2, 78.1, 114.2, 126.0,
126.3, 131.2, 131.9, 132.2, 133.2, 133.7, 143.8, 153.8, 181.4, 185.0;
HRESIMS m/z 267.1015 [MþH]þ (Calcd for C17H15O3þ: 267.1016).
Fellowships granted to V.F.F. by CNPq (Brazil), D.R.R. by CAPES-
FAPERJ and S.B.F. by CAPES are gratefully acknowledged. This work
was partially supported by CNPq grant 471588/2009-1, FAPERJ-
PRONEX grant number 110.574/2010.
References and notes
4.2.4.3. 2-Allyl-3-(allyloxy)naphthalene-1,4-dione
40%; yellow oil. IR (KBr, cmꢂ1):
3077, 2924, 1671, 1655, 1607, 1595,
1578, 1458, 1423, 1337, 1303, 1264, 1231, 1196, 1043, 994; 1H NMR
(CDCl3, 500 MHz): 3.30e3.32 (2H, m), 4.84e4.86 (2H, m), 4.97
(11). Yield:
1. Bowers, R. S.; Ohta, T.; Cleere, J. S.; Marsella, P. A. Science 1976, 193, 542.
2. Ellis, G. P. The Chemistry of Heterocyclic Compounds; John Wiley & Sons: New
York, NY, 1977; Vol. 31, pp 1e10.
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Crogan-Grundy, C.; Denis, R.; Barriault, N.; Vaillancourt, L.; Charron, S.; Dodd, J.;
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1996, 4, 1755.
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Morris-Natschke, S. L.; Lee, K. H. Tetrahedron 2001, 57, 1559.
7. Zhang, X.; Li, X.; Sui, Z. EP1846397, 2007.
n
d
(1H, dd, J¼1.5, 9.8 Hz), 5.07 (1H, dd, J¼1.5, 17.1 Hz), 5.20 (1H, dd,
J¼1.0, 10.3 Hz), 5.31 (1H, dd, J¼1.5, 17.1 Hz), 5.76e5.84 (1H, m),
5.94e6.02 (1H, m), 7.60e7.65 (1H, m), 7.60e7.65 (1H, m), 7.96e8.01
(1H, m), 7.96e8.01 (1H, m); 13C NMR (CDCl3, 125 MHz): 27.9, 74.0,
116.4, 118.6, 126.0, 126.1, 131.3, 131.8, 133.1, 133.2, 133.4, 133.7, 134.1,
156.8, 181.5, 184.8.
4.2.5. General procedure for the metathesis reaction. A solution of
9e11 (1 mmol) and second generation Grubbs catalyst (10% mol,
0.01 mmol) in degassed dry dichloromethane (5 mL) was heated at
reflux under argon. After 30 min at reflux, the reaction mixture was
cooled to room temperature, the solvent was evaporated, and the
residue was purified by flash chromatography using a gradient of
toluene/EtOAc as the eluent.
8. Kidwai, M.; Saxena, S.; Khan, M. K. R.; Thukral, S. S. Bioorg. Med. Chem. Lett.
2005, 15, 4295.
ꢀ
9. Batista, J. M., Jr.; Lopes, A. A.; Ambrosio, D. L.; Regasini, L. O.; Kato, M. J.; Bolzani,
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10. Verma, R. K.; Prajapati, V. K.; Verma, G. K.; Chakraborty, D.; Sundar, S.; Rai, M.;
Dubey, V. K.; Singh, M. S. ACS Med. Chem. Lett. 2012, 3, 243.
11. Oliveira, A. B.; Raslan, D. S.; Miraglia, M. C. M.; Mesquita, A. A. L.; Zani, C. L.;
Ferreira, D. T.; Maia, J. G. S. Quim. Nova 1990, 13, 302.
12. Hannedouche, S.; Souchard, J. P.; Jacquemond-Collet, I.; Moulis, C. Fitoterapia
2002, 73, 520.
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J. C. Pest Manage. Sci. 2006, 62, 414.
14. Gonc¸ alves, L. O.; D’Albuquerque, I. L.; Lima, C. G.; Maia, M. H. D. Rev. Inst.
Antibiot. 1962, 4, 3.
15. Machado, T. B.; Pinto, A. V.; Pinto, M. C. F. R.; Leal, I. C. R.; Silva, M. G.;
Amaral, A. C. F.; Kuster, R. M.; Netto dos Santos, K. R. Int. J. Antimicrob. Agents
2003, 21, 279.
16. Dudley, K. H.; Chiang, R. W. J. Org. Chem. 1969, 34, 120.
17. Ferreira, V. F.; Pinto, A. V.; Coutada, L. C. M. An. Acad. Bras. Cienc. 1980, 52, 478.
18. de Oliveira, A. B.; Ferreira, D. T.; Raslan, D. S. Tetrahedron Lett. 1988, 29, 155.
19. Lee, Y. R.; Lee, W. K. Synth. Commun. 2004, 34, 4537.
20. Lee, Y. R.; Choi, J. H.; Trinh, D. T. L.; Kim, N. W. Synthesis 2005, 3026.
21. Wang, X.; Chen, Y.; Lee, Y. R. Bull. Korean Chem. Soc. 2011, 32, 153.
22. Kumar, S.; Malachowski, W. P.; DuHadaway, J. B.; LaLonde, J. M.; Carroll, P. J.;
Jaller, D.; Metz, R.; Prendergast, G. C.; Muller, A. J. J. Med. Chem. 2008, 51, 1706.
23. Chauder, B. A.; Lopes, C. C.; Lopes, R. S. C.; da Silva, A. J. M.; Snieckus, V.
Synthesis 1998, 279.
24. (a) Ferreira, S. B.; da Silva, F. de C.; Bezerra, F. A. F. M.; Lourenc¸ o, M. C. S.; Kaiser,
C. R.; Pinto, A. C.; Ferreira, V. F. Arch. Pharm. (Weinheim, Ger.) 2010, 343, 81; (b)
Freire, C. P. V.; Ferreira, S. B.; de Oliveira, N. S. M.; Matsuura, A. B. J.; Gama, I. L.;
da Silva, F. C.; de Souza, M. C. B. V.; Lima, E. S.; Ferreira, V. F. Med. Chem.
Commun. 2010, 1, 229; (c) da Silva, M. N.; Ferreira, S. B.; Jorqueira, A.; de Souza,
M. C. B. V.; Pinto, A. V.; Kaiser, C. R.; Ferreira, V. F. Tetrahedron Lett. 2007, 48,
6171; (d) Ferreira, S. B.; Kaiser, C. R.; Ferreira, V. F. Org. Prep. Proced. Int. 2009, 41,
211.
4.2.5.1. 2H-Benzo[g]chromene-5,10-dione (5m). Yield: 73%; red
solid; mp: 162 ꢁC. IR (KBr, cmꢂ1):
n
2921, 1671, 1647, 1587, 1334,
1299, 1253, 1196, 1114, 996, 940, 794, 714, 671; 1H NMR (CDCl3,
500 MHz):
d
5.03 (2H, dd, J¼2.0, 3.5 Hz), 5.81 (1H, dt, J¼3.5,
10.0 Hz), 6.66 (1H, dt, J¼2.0, 10.0 Hz), 7.59e7.68 (1H, m), 7.59e7.68
(1H, m), 8.00e8.03 (1H, m), 8.00e8.03 (1H, m); 13C NMR (CDCl3,
125 MHz): 67.2, 117.6, 119.0, 122.2, 126.1, 126.0, 131.2, 131.1, 133.2,
133.9, 153.3, 179.2, 181.4; HRESIMS m/z 213.0538 [MþH]þ (Calcd for
C
13H9O3þ: 213.0546).
4.2.5.2. 3-(2-Methylprop-1-enyl)-2H-benzo[g]chromene-5,10-di-
one (5n). Yield: 88%; purple solid; mp: 153e154 ꢁC. IR (KBr, cmꢂ1):
n
1666, 1648, 1608, 1591, 1560, 1351, 1340, 1215, 1195, 720; 1H NMR
(CDCl3, 500 MHz): 1.83 (3H, s), 1.87 (3H, s), 4.98 (2H, s), 5.57 (1H,
d
s), 6.47 (1H, s), 7.59e7.65 (1H, m), 7.59e7.65 (1H, m), 8.00e8.02
(1H, m), 8.00e8.02 (1H, m); 13C NMR (CDCl3, 125 MHz): 20.8, 27.6,
69.5, 113.5, 120.8, 121.3, 125.9, 126.1, 131.3, 131.4, 132.4, 133.1, 133.6,
142.1, 151.0, 178.8, 181.9; HRESIMS m/z 267.1012 [MþH]þ (Calcd for
C
17H15O3þ: 267.1016).
25. Kongkathip, N.; Kongkathip, B.; Siripong, P.; Sangma, C.; Luangkamin, S.;
Niyomdecha, M.; Pattanapa, S.; Piyaviriyagul, S.; Kongsaeree, P. Bioorg. Med.
Chem. 2013, 11, 3179.
4.2.5.3. Naphtho[2,3-b]oxepine-6,11(2H,5H)-dione
(6). Yield:
2922, 2852,
54%; yellow solid; mp: 125e126 ꢁC. IR (KBr, cmꢂ1):
n
26. Glazunov, V. P.; Berdyshev, D. V.; Yakubovskaya, A.; Pokhilo, N. D. Russ. Chem.
1675,1288, 1247, 1194, 1060, 1017, 723; 1H NMR (CDCl3, 500 MHz):
Bull. 2006, 55, 1729.
d
3.56 (2H, d, J¼5.9 Hz), 4.84 (2H, d, J¼5.9 Hz), 5.97e6.01 (1H, m),
27. Fieser, L. F.; Fieser, M. J. Am. Chem. Soc. 1948, 70, 3215.