A facile, three-component domino protocol for the microwave-assisted synthesis of functionalized naphtho[2,3-b]furan-4,9-diones in water

Article abstract of DOI:10.1039/c0gc00952k

A three-component domino reaction of 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes and a pyridinium salt in the presence of ammonium acetate, under microwave irradiation and using water as solvent, furnished a library of novel 2-arylcarbonyl-3-aryl-4,9

Full text of DOI:10.1039/c0gc00952k

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PAPER
A facile, three-component domino protocol for the microwave-assisted
synthesis of functionalized naphtho[2,3-b]furan-4,9-diones in water†
Pitchaimani Prasanna,a Kamaraj Balamurugan,a Subbu Perumal*a and J. Carlos Mene´ndez*b
Received 25th December 2010, Accepted 21st April 2011
DOI: 10.1039/c0gc00952k
A three-component domino reaction of 2-hydroxy-1,4-naphthoquinone, aromatic aldehydes and a
pyridinium salt in the presence of ammonium acetate, under microwave irradiation and using
water as solvent, furnished a library of novel 2-arylcarbonyl-3-aryl-4,9-dihydronaphtho-
[2,3-b]furan-4,9-diones in good yields, in a transformation that presumably proceeds via an
a,b-unsaturated triketone generation/Michael addition/intramolecular cyclisation/air oxidation
one-pot sequence.
important challenge for green chemistry, that is only beginning
Introduction
to be met.8
The conventional multistep methods for the preparation of
The naphtho[2,3-b]furan-4,9-dione skeleton belongs to a well-
complex molecules involve a large number of synthetic oper-
known and important class of heterocyclic quinones9 prevalent
ations, including extraction and purification processes for each
in a number of natural products of biological importance
individual step, that lead to synthetic inefficiency and the gen-
eration of large amounts of waste. Multicomponent reactions
(Fig. 1).10 For instance, naphthofuroquinones 1–3, isolated
from Tabebuia cassinoides, display anticancer activity,11 which
(MCRs) allow the creation of several bonds in a single operation
has also been found in a large number of related synthetic
and offer remarkable advantages like convergence, operational
compounds.12 Kigelinone 4, from the fruits of Kigelia pinnata,
simplicity, facile automation, reduction in the number of work-
possesses antibacterial,13 antifungal and antiviral activities,14
ups, extraction and purification processes, and hence minimized
and several synthetic naphthofuroquinones show antiprotozoal
waste generation rendering the transformations green. MCRs
are useful for the expedient creation of chemical libraries of
properties.15 Maturone 5 and maturinone 6 are isolated from
Cacalia decomposita, whose root extract has been used for the
drug-like compounds with high levels of molecular complexity
treatment of diabetes.16 Naphthofuroquinones have also been
and diversity,1 thereby facilitating expedient lead identifica-
identified as components of medicinal preparations widely used
tion/optimization in drug discovery programmes.2
in North and South America.
Another important aspect of green chemistry pertains to the
elimination of volatile organic solvents or their replacement by
non-flammable, non-volatile, non-toxic and inexpensive “green
solvents”.3 Water complies all these stringent requirements and
often exhibits important rate enhancements,4 unique selectivity
and reactivity.5 Consequently, the development of synthetically
useful reactions in water is of considerable interest.6,7 In this
context, the design of synthetic routes to privileged heterocyclic
scaffolds of medicinal relevance that combine the synthetic
efficiency of multicomponent protocols with the environmental
benefits of using water as the reaction medium constitutes a very
aDepartment of Organic Chemistry, School of Chemistry, Madurai
Fig. 1 Some natural, bioactive naphtho[2,3-b]furan-4,9-diones.
Kamaraj University, Madurai, 625021, India.
E-mail: subbu.perum@gmail.com; Fax: +91 452-2459845
bDepartamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de
The first naphtho[2,3-b]furan-4,9-dione was synthesised from
Farmacia, Universidad Complutense, 28040, Madrid, Spain.
2-hydroxy-l,4-naphthoquinone via a multistep approach.17 More
E-mail: josecm@farm.ucm.es; Fax: +34 91-3941822
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c0gc00952k
recent methods include [3 + 2]-cycloaddition-based protocols
involving C- and O-alkylations of naphthoquinones by 1,
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3-dicarbonyl
compounds,18
CAN-promoted
oxidative
reactions19 or [3 + 2] photoadditions,20 Pd- or Cu-catalysed
sequential coupling/annulation,21 tandem O-Michael-carbene
insertion,22 condensation-[4 + 1]cycloaddition or [3 + 1 +
1]furoannulation23 and a number of multistep strategies.24 Most
of these are multistep protocols, that suffer from generation of
by-products, low yields and use of metal-containing reagents.
Therefore, efficient new synthetic methods employing non-toxic
reagents and solvents are highly desirable from the viewpoint
of green chemistry. We describe in this paper our findings on
the synthesis of functionalized naphtho[2,3-b]furan-4,9-diones
using a three-component domino protocol in water.
Fig. 2 Structure of compound 10a obtained during optimization
studies.
under microwave irradiation, using the previously mentioned
conditions. We were also encouraged to undertake this study
by the fact that the use of microwave irradiation in sealed
vessels has been proven to be accompanied by energy savings,
probably associated mainly to the shortened reaction time,27
although it has been recently shown that improvements in energy
efficiency are significant only for industrial-scale applications
involving multimode reactors.28 In search for a greener solvent,
the reaction was performed in N,N-dimethylformamide (DMF),
methanol, ethanol, ethylene glycol and water (entries 2–6).
Gratifyingly, we found that the reaction in water furnished the
maximum yield of the product (86%) in only 20 min (entry
6), and hence all subsequent experiments were performed in
this medium. The model reaction was also investigated employ-
ing different bases, viz. sodium acetate, potassium carbonate,
triethylamine, diethylamine, L-proline and morpholine (entries
7–12), and the results show that the initial ammonium acetate–
water combination was ideal for the reaction. To the best of
our knowledge, domino reactions employing pyridinium ylides
generated in situ for the construction of 2-aroyl-3-aryl-4,9-
dihydronaphtho[2,3-b]furan-4,9-diones in water medium have
not been reported yet.
Results and discussion
As shown in Scheme 1 and Table 1, we started our study
with the optimization of the three-component reaction between
2-hydroxy-1,4-naphthoquinone 7 (1 mmol), benzaldehyde 8a
(1 mmol) and 1-(2-oxo-2-phenylethyl)pyridinium bromide 9
(1 mmol) in the presence of ammonium acetate (5 mmol) in
acetonitrile under reflux for 10 h, which afforded 2-benzoyl-
3-phenyl-4,9-dihydronaphtho[2,3-b]furan-4,9-dione 10a in 68%
yield (Fig. 2).
Having established the optimal conditions, we explored the
scope and generality of the method by preparing a library
of hitherto unreported 2-aroyl-3-aryl-4,9-dihydronaphtho[2,3-
b]furan-4,9-diones 10 (Scheme 1 and Table 2). Typically, a
mixture of 2-hydroxy-1,4-naphthoquinone 7, aromatic aldehyde
8, 1-(2-oxo-2-arylethyl)pyridinium bromide 9 and NH4OAc
(1 : 1 : 1 : 5 mmol) in a sealed vial was irradiated in a focused
microwave oven at 130 ◦C and 150 W for 20 min. After
Scheme 1 Synthesis of 2-aroyl-3-arylnaphtho[2,3-b]furan-4,9-diones
10.
Because of the advantages of the use of microwave
irradiation,25,26 we also studied this model reaction under focused
microwave irradiation in sealed vessels at 130 ◦C and 150 W
for 20 min, and obtained 10a in 79% yield (entry 1, Table 1),
which encouraged us to carry out all our subsequent studies
Table 2 Synthesis of compounds 10: comparison between conventional
and microwave-assisted reactions
Yield (%)a
Table 1 Solvent- and base-screen for the synthesis of compound 10a
under microwave irradiation
Entry Compound Ar
Ar1
Thermal Microwave
Entry
Base
Solvent
Time, min
Yield,%a
1
2
3
4
5
6
7
8
10a
10b
10c
10d
10e
10f
10g
10h
10i
C6H5
C6H5
C6H5
C6H5
C6H5
73
73
74
75
81
74
66
80
71
86
80
82
81
86
76
74
84
79
80
77
83
78
81
77
4-MeC6H4
4-ClC6H4
4-FC6H4
1
2
3
4
5
6
7
8
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NH4OAc
NaOAc
K2CO3
Et3N
Et2NH
L-Proline
Morpholine
CH3CN
DMF
MeOH
EtOH
Ethylene glycol
Water
Water
Water
Water
Water
Water
20
25
25
20
25
20
20
20
25
25
20
20
79
41
57
63
74
86
59
47
32
42
0b
4-O2NC6H4 C6H5
C6H5
4-ClC6H4
4-PriC6H4
4-ClC6H4
4-FC6H4
4-ClC6H4
4-FC6H4
C6H5
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4 75
4-MeC6H4 68
2-Naphthyl 77
2-Naphthyl 70
2-Naphthyl 74
2-Naphthyl 71
9
10
11
12
13
14
15
10j
9
10k
10l
10m
10n
10o
10
11
12
4-iPrC6H4
4-ClC6H4
3-FC6H4
Water
0b
a Isolated yield after purification. A 68% yield was obtained after 10 h
in refluxing acetonitrile. b No reaction was found.
a Isolated yield after purification.
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completion of the reaction (TLC), the products 10 were isolated
and purified by simple filtration through a pad of silica gel.
For comparison purposes, the reactions were also performed
at 100 ◦C in water for 10 h. Although the overall yields
obtained for both cases can be considered excellent bearing
in mind the large number of steps involved in the domino
sequence, the yield of the reaction was consistently enhanced
under microwave irradiation (74–86%, compared to 66–81%
under conventional heating conditions). Other advantages of
the microwave-promoted conditions include the dramatically
shorter reaction time and lower energy requirements. Thus,
the energy efficiency of both sets of conditions was studied
for the synthesis of compound 10a, for which the energy
consumption under microwave-assisted and thermal conditions
was determined experimentally by using a watt-meter and found
to be ca. eight times lower for the former (0.13 kWh vs.
1.03 kWh).
Fig. 3 1H and 13C NMR assignment in compound 10b, as a represen-
tative example.
with other catalysts. Then, the Michael addition of pyridinium
ylide 15 (generated in situ from 9) to 14 presumably affords the
pyridinium enolate 16, which subsequently undergoes annula-
tion via displacement of pyridine to give 17, which is probably
in tautomeric equilibrium with the corresponding hydroquinone
18. Ultimately, these intermediates are transformed into the final
products 10 via air oxidation. Overall, this three-component
domino transformation leads to the generation of one C–O and
two C–C bonds.
The structures of the naphtho[2,3-b]furan-4,9-diones 10a–10o
1
were fully characterized by H and 13C NMR, IR and mass
spectroscopicdata andelementalanalysis. For example, inthe 1H
NMR spectrum of 10b, the H-3¢ and H-2¢ showed two doublets
with J = 8.1 Hz at 7.21 and 7.40 ppm (Fig. 3). The H-3¢¢,5¢¢
showed a triplet at 7.43 ppm (J = 7.8 Hz), whilst the H-2¢¢,6¢¢
appeared as a doublet of doublets at 7.92 ppm (J = 8.1 and
1.2 Hz). The H-4¢¢ appeared as a multiplet at 7.55–7.60 ppm. The
multiplet in the chemical shift range of 7.79–7.82 ppm is assigned
to H-6 and H-7. The H-5 and H-8 showed multiplets at 8.16–
8.19 ppm and 8.26–8.29 ppm in view of their proximity to the
adjacent carbonyl groups. The chemical shifts of the hydrogens
and the respective C,H-COSY correlations allowed to assign the
connected carbon chemical shifts (Fig. 3).
Conclusions
In conclusion, a facile one-pot, three-component reaction
for the efficient assembly of naphtho[2,3-b]furan-4,9-diones,
structurally related to medicinally important compounds, via
an aldol (Mannich)/Michael addition/annulation via nucle-
ophilic displacement/air oxidation domino sequence in water
is described. The present work constitutes the first report of
the synthesis of dihydrofurans employing the enol form of a
triketone, viz. 2-hydroxy-1,4-naphthoquinone with pyridinium
ylide generated in situ from the reaction of phenacylpyridinium
salt.29 Furthermore, our protocol employs focused microwave
irradiation and water as a green solvent.
A plausible mechanism for the formation of naphtho[2,3-
b]-furan-4,9-diones 10 is depicted in Scheme 2. Presumably,
the intermediate 3-[1-arylmethylidene]-1,2,3,4-tetrahydro-1,2,4-
naphthalenetriones 14 could arise in two ways: (i) via the
Mannich reaction of 2-hydroxy-1,4-naphthoquinone 7 with an
iminium ion 11 generated from 8 and ammonium acetate,
followed by elimination of ammonia, or (ii) the ammonium
acetate-catalyzed reaction of 7 with the starting aldehyde
to afford aldol 13, which would undergo dehydration. The
mechanism involving an iminium ion presumably explains the
higher yield obtained in presence of ammonium acetate than
Experimental
Melting points were measured in open capillary tubes and are
uncorrected. A CEM Discover microwave synthesizer (Model
Scheme 2 Probable domino sequence leading to the formation of 10.
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No: 908010) operating at 180/264 V and 50/60 Hz with
microwave power maximum level of 300 W and microwave
frequency of 2455 MHz was employed for the microwave-
assisted experiments done in this work. The 1H NMR, 13C NMR
and C,H-COSY spectra were recorded on a Bruker (Avance)
300 MHz NMR instrument using TMS as internal standard
and CDCl3 as solvent. Standard Bruker software was used
throughout. Chemical shifts are given in parts per million (d-
scale) and the coupling constants are given in Hertz. Silica gel-
G plates (Merck) were used for TLC analysis with a mixture
of petroleum ether (60–80 ◦C) and ethyl acetate as eluent.
Elemental analyses were performed on a Perkin Elmer 2400
Series II Elemental CHNS analyzer. IR spectra were recorded
on a JASCO FT IR instument (KBr pellet method). HRMS
measurements were performed by the CAI de Espectrometria
de Mass, Universidad Complutense, using an FTMS Bruker
APEX QIV instrument. Energy consumption for thermal and
microwave irradiation reactions have been determined using a
wattmeter manufactured by H. Brennenstuhl GmbH & Co. KG-
D-72074 Tubingen (Model PM 240 S-D, 230V AC-50 Hz max.
16A/3680W).
378.08921. Found: 378.08976. Anal. calcd for C25H14O4: C,
79.36; H, 3.73%. Found: C, 79.29; H, 3.66%.
2-Benzoyl-3-(4-methylphenyl)-4,9-dihydronaphtho[2,3-b]fu-
rane-4,9-dione (10b). Yellow solid; Yield: 80% (MW), 73%
(Thermal); m.p. 154–155 ◦C; IR (KBr): 1681, 1621, 1348, 1267
cm-1; 1H NMR (300 MHz, CDCl3) dH: 2.41 (s, 3H, CH3), 7.21 (d,
2H, J = 8.1 Hz, Ar–H), 7.40 (d, 2H, J = 8.1 Hz, Ar–H), 7.44(d,
2H, J = 7.8 Hz, Ar–H), 7.54–7.59 (m, 1H, Ar–H), 7.78–7.81
(m, 2H, Ar–H), 7.92 (dd, 2H, J = 8.4, 1.2 Hz, Ar–H), 8.16–8.19
(m, 1H, Ar–H), 8.25–8.28 (m, 1H, Ar–H); 13C NMR (75 MHz,
CDCl3) dC: 21.3, 125.1, 126.8, 127.2, 127.8, 128.4, 128.6, 129.8,
130.0, 132.0, 132.3, 133.5, 133.8, 133.9, 134.3, 136.0, 139.1,
150.4, 152.3, 174.0, 179.8, 183.7. HRMS (positive ESI): m/z
calcd for C26H16O4 + Na+: 415.09463. Found: 415.09408. Anal.
calcd for C26H16O4: C, 79.58; H, 4.11%. Found: C, 79.50; H,
4.05%.
2-Benzoyl-3-(4-chlorophenyl)-4,9-dihydronaphtho[2,3-b]fur-
ane-4,9-dione (10c). Yel◦low solid; Yield: 82% (MW), 74%
(Thermal); m.p. 242–243 C; 1H NMR (300 MHz, CDCl3) dH:
7.37 (d, 2H, J = 8.7 Hz, Ar–H), 7.43–7.48 (m, 4H, Ar–H), 7.57–
7.63 (m, 1H, Ar–H), 7.74–7.83 (m, 2H, Ar–H), 7.92 (d, 2H, J =
8.7 Hz, Ar–H), 8.13–8.18 (m, 1H, Ar–H), 8.24–8.29 (m, 1H, Ar–
H); 13C NMR (75 MHz, CDCl3) dC: 126.6, 126.9, 127.3, 127.6,
128.1, 128.6, 129.8, 130.7, 131.5, 132.2, 133.6, 133.7, 134.1,
134.5, 135.3, 135.8, 150.5, 152.3, 173.8, 179.8, 183.4. HRMS
(positive ESI): m/z calcd for C25H13ClO4 + Na+: 435.04001 (M+)
and 437.03706 (M + 2)+. Found: 435.03946 and 437.03651. Anal.
calcd for C25H13ClO4: C, 72.74; H, 3.17%. Found: C, 72.66; H,
3.11%.
General procedure for synthesis of naphtho[2,3-b]-furane-4,9-
dione derivatives 10
Conventional heating method. A mixture of 2-hydroxy-1,4-
naphthoquinone 7 (0.300 g, 1.72 mmol), the suitable aromatic
aldehyde (1.72 mmol), 1-(2-oxo-2-phenylethyl)pyridinium bro-
mide 9 (0.479 g, 1.72 mmol), and NH4OAc (0.663 g, 8.6 mmol)
in water (10 mL) was refluxed in an oil bath for 10 h. After
completion of the reaction (TLC), the product was extracted
with ethyl acetate (10 ml) and purified by filtration through a
pad of silica gel using a 3 : 1 AcOEt-petroleum ether mixture, to
yield pure 10.
2-Benzoyl-3-(4-fluorophenyl)-4,9-dihydronaphtho[2,3-b]fur-
ane-4,9-dione (10d). Yellow solid; Yield: 81% (MW), 75%
(Thermal); m.p. 166–167 ◦C; IR (KBr): 1741, 1677, 1646, 1486,
1442 cm-1; 1H NMR (300 MHz, CDCl3) dH: 7.06–7.12 (m, 1H,
Ar–H), 7.26–7.30 (m, 1H, Ar–H), 7.42–7.53 (m, 4H, Ar–H),
7.57–7.62 (m, 1H, Ar–H), 7.80–7.84 (m, 2H, Ar–H), 7.92 (d,
2H, J = 8.4 Hz, Ar–H), 8.17–8.20 (m, 1H, Ar–H), 8.26–8.31
(m, 1H, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 115.6, 124.1,
126.9, 127.3, 127.7, 128.6, 129.9, 130.2, 131.0, 132.3, 133.8,
134.1, 134.2, 134.5, 136.0, 150.6, 152.4, 163.3, 174.0, 180.0,
183.6. HRMS (positive ESI): m/z calcd for C25H13FO4 + Na+:
419.06956. Found: 419.06901. Anal. calcd for C25H13FO4: C,
75.75; H, 3.31%. Found: C, 75.68; H, 3.37%.
Microwave irradiation method. A vial containing a mixture
of 2-hydroxy-1,4-naphthoquinone 7 (0.300 g, 1.72 mmol), aro-
matic aldehyde (1.72 mmol), 1-(2-oxo-2-phenylethyl)pyridinium
bromide 9 (0.479 g, 1.72 mmol), and NH4OAc (0.663 g,
8.60 mmol) in water (7 ml) was sealed and placed in a CEM
Discover microwave oven. The vi◦al was subjected to microwave
irradiation, programmed at 130 C and 150 W. After a period
of 3–5 min, the temperature reached a plateau, 130 ◦C, and
remained constant. After completion of the reaction (20 min),
the vial was cooled to room temperature and extracted with ethyl
acetate (10 ml) and purified by filtration through a pad of silica
gel using a 3 : 1 AcOEt–petroleum ether mixture, to yield pure
10. Characterization data of all compounds are given below.
2-Benzoyl-3-(4-nitrophenyl)-4,9-dihydronaphtho[2,3-b]furane-
4,9-dione (10e). Yellow solid; Yield: 86% (MW), 81% (Ther-
mal); m.p. 237–238 ◦C; IR (KBr): 1679, 1671, 1654, 1348, 1230
cm-1; 1H NMR (300 MHz, CDCl3) dH: 7.50 (t, 2H, J = 7.5 Hz,
Ar–H), 7.64 (t, 1H, J = 7.5 Hz, Ar–H), 7.70 (d, 2H, J = 8.7 Hz,
Ar–H), 7.82–7.85 (m, 2H, Ar–H), 8.00 (d, 2H, J = 7.2 Hz, Ar–H),
8.16–8.18 (m, 1H, Ar–H), 8.28–8.31 (m, 3H, Ar–H); 13C NMR
(75 MHz, CDCl3) dC: 123.1, 127.1, 127.4, 127.7, 128.8, 129.8,
130.0, 131.3, 132.3, 133.6, 134.2, 134.4, 134.7, 135.3, 135.7,
148.2, 150.9, 152.4, 173.8, 179.8, 183.1. HRMS (positive ESI):
m/z calcd for C25H13NO6 + Na+: 446.06406. Found: 446.06351.
Anal. calcd for C25H13NO6: C, 70.92; H, 3.09; N, 3.31%. Found:
C, 70.86; H, 3.02; N, 3.25%.
2-Benzoyl-3-phenyl-4,9-dihydronaphtho[2,3-b]furane-4,9-di-
one (10a). Yellow solid; Yield: 86% (MW), 73% (Thermal);
m.p. 137–138 ◦C; IR (KBr): 1681, 1587, 1436, 1357, 1322 cm-1;
1H NMR (300 MHz, CDCl3) dH: 7.32-7.34 (m, 4H, Ar–H),
7.40-7.43 (m, 2H, Ar–H), 7.48 (t, 2H, Ar–H), 7.71-7.74 (m, 2H,
Ar–H), 7.82 (d, 2H, J = 7.8 Hz, Ar–H), 8.08-8.11 (m, 1H, Ar–H),
8.18-8.21 (m, 1H, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 126.8,
127.2, 127.7, 127.8, 128.2, 128.4, 129.0, 129.8, 130.1, 131.7,
132.3, 133.5, 133.7, 133.9, 134.4, 136.0, 150.5, 152.3, 173.9,
179.8, 183.6. HRMS (negative ESI): m/z calcd for C25H14O4,
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2-(4-Chlorobenzoyl)-3-phenyl-4,9-dihydronaphtho[2,3-b]fur-
ane-4,9-dione (10f). Yellow solid; Yield: 76% (MW), 74%
(Thermal); m.p. 208–209 ◦C; IR (KBr): 1743, 1691, 1529, 1295
cm-1; 1H NMR (300 MHz, CDCl3) dH: 7.26 (s, 1H, Ar–H), 7.40
(d, 2H, J = 8.7 Hz, Ar–H), 7.42–7.43 (m, 2H, Ar–H), 7.47–
7.50 (m, 2H, Ar–H), 7.79–7.82 (m, 2H, Ar–H), 7.87 (d, 2H, J =
8.7 Hz, Ar–H), 8.16–8.19 (m, 1H, Ar–H), 8.26–8.29 (m, 1H,
Ar–H); 13C NMR (75 MHz, CDCl3) dC: 126.8, 127.3, 127.7,
127.9, 128.0, 128.8, 129.2, 130.1, 131.2, 132.2, 133.7, 134.0,
134.3, 134.4, 140.2, 150.1, 152.4, 173.9, 179.7, 182.2. HRMS
(positive ESI): m/z calcd for C25H13ClO4 + Na+: 435.04001 (M+)
and 437.03706 (M + 2)+. Found: 435.03946 and 437.03651. Anal.
calcd for C25H13ClO4: C, 72.74; H, 3.17%. Found: C, 72.66; H,
3.21%.
1355, 1218 cm-1; 1H NMR (300 MHz, CDCl3) dH: 2.43 (s, 3H,
CH3), 7.25–7.28 (m, 2H, Ar–H), 7.39 (d, 2H, J = 8.7 Hz, Ar–H),
7.47 (d, 2H, J = 8.7 Hz, Ar–H), 7.79–7.81 (m, 2H, Ar–H), 7.85 (d,
2H, J = 8.4 Hz, Ar–H), 8.16–8.19 (m, 1H, Ar–H), 8.26–8.29 (m,
1H, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 21.7, 126.8, 126.9,
127.2, 127.3, 127.7, 128.2, 129.4, 129.6, 129.9, 130.1, 130.4,
131.6, 132.3, 133.4, 133.8, 134.1, 134.5, 135.3, 145.1, 150.9,
152.3, 173.9, 179.9,183.1. HRMS (positive ESI): m/z calcd for
C26H15ClO4 + Na+: 449.05566 (M+), 451.05271 (M + 2)+. Found:
449.05511, 451.05216. Anal. calcd for C26H15ClO4: C, 73.16; H,
3.54%. Found: C, 73.09; H, 3.48%.
3-(4-Fluorophenyl)-2-(4-methylbenzoyl)-4,9-dihydronaphtho-
[2,3-b]furane-4,9-dione (10k). Yellow solid; Yield: 77% (MW),
68% (Thermal); m.p. 231–232 ◦C; nmax(KBr): 1756, 1683, 1621,
1348, 1295 cm-1; 1H NMR (300 MHz, CDCl3) dH: 7.02–7.08 (m,
2H, Ar–H), 7.19–7.21 (m, 2H, Ar–H), 7.44–7.49 (m, 2H, Ar–H),
7.74–7.77 (m, 2H, Ar–H), 7.79 (d, 2H, J = 8.1 Hz), 8.11–8.14
(m, 1H, Ar–H), 8.21–8.24 (m, 1H, Ar–H); 13C NMR (75 MHz,
CDCl3) dC: 21.7, 115.0, 124.2, 124.3, 126.9, 127.3, 127.7, 129.3,
130.1, 130.5, 132.2, 133.4, 133.8, 134.1, 134.5, 145.0, 150.9,
152.3, 164.7, 174.0, 180.0, 183.2. HRMS (positive ESI): m/z
calcd for C26H15FO4 + Na+: 433.08521 (M+). Found: 433.08466.
Anal. calcd for C26H15FO4: C, 76.09; H, 3.68%. Found: C, 76.02;
H, 3.60%.
2-(4-Chlorobenzoyl)-3-(4-isopropylphenyl)-4,9-dihydro napht-
ho[2,3-b]furane-4,9-dione (10g). Yellow solid; Yield: 74%
(MW), 66% (Thermal); m.p. 188–189 ◦C; IR (KBr): 1679, 1658,
1
1589, 1357, 1326 cm-1; H NMR (300 MHz, CDCl3) dH: 1.27
(d, 6H, J = 6.9 Hz, CH3), 2.89–3.00 (m, 1H, CH), 7.21 (d, 2H,
J = 9.0 Hz, Ar–H), 7.32–7.39 (m, 4H, Ar–H), 7.76–7.82 (m, 4H,
Ar–H), 8.17–8.20 (m, 1H, Ar–H), 8.26–8.29 (m, 1H, Ar–H); 13
C
NMR (75 MHz, CDCl3) dC: 23.8, 34.0, 125.2, 126.0, 126.9,
127.4, 127.8, 128.8, 130.3, 131.2, 132.3, 132.5, 133.9, 134.0,
134.5, 140.0, 150.2, 150.3, 152.7, 174.0, 179.9, 182.6. HRMS
(positive ESI): m/z calcd for C28H19ClO4 + Na+: 477.08696 (M+)
and 479.08401 (M+ + 2). Found: 477.08641 and 479.08346. Anal.
calcd for C28H19ClO4: C, 73.93; H, 4.21%. Found: C, 73.87; H,
4.14%.
2-(2-Naphthylcarbonyl)-3-phenyl-4,9-dihydronaphtho[2,3-b]-
furane-4,9-dione (10l). Yellow solid; Yield: 83% (MW), 77%
(Thermal); m.p. 233–234 ◦C; IR (KBr): 1670, 1665, 1587, 1357,
1267 cm-1; 1H NMR (300 MHz, CDCl3) dH: 7.23–7.27 (m, 2H,
Ar–H), 7.33–7.37 (m, 2H, Ar–H), 7.52–7.65 (m, 3H, Ar–H),
7.80–7.85 (m, 3H, Ar–H), 7.88–7.98 (m, 3H, Ar–H), 8.19–8.21
(m, 1H, Ar–H), 8.28–8.29 (m, 1H, Ar–H), 8.45 (s, 1H, Ar–
H); 13C NMR (75 MHz, CDCl3) dC: 124.7, 126.8, 126.9, 127.3,
127.8, 127.9, 128.3, 128.5, 129.0, 129.1, 129.8, 130.2, 131.7,
132.3, 132.4, 132.6, 133.3, 133.9, 134.0, 134.4, 135.8, 150.9,
152.5, 174.0, 179.9, 183.6. HRMS (positive ESI): m/z calcd for
C29H16O4 + Na+: 451.09463 (M+). Found: 451.09461. Anal. calcd
for C29H16O4: C, 81.30; H, 3.76%. Found: C, 81.23; H, 3.70%.
2-(4-Chlorobenzoyl)-3-(4-chlorophenyl)-4,9-dihydronaphtho-
[2,3-b]furan-4,9-dione (10h). Yellow solid; Yield: 84% (MW),
80% (Thermal); m.p. 246–247 ◦C; IR (KBr): 1683, 1689, 1527,
1
1348, 1299 cm-1; H NMR (300 MHz, CDCl3) dH: 7.26–7.29
(m, 1H, Ar–H), 7.40–7.49 (m, 5H, Ar–H), 7.80–7.83 (m, 2H,
Ar–H), 7.93 (d, 2H, J = 8.7 Hz, Ar–H), 8.16–8.19 (m, 1H,
Ar–H), 8.26–8.30 (m, 1H, Ar–H); 13C NMR (75 MHz, CDCl3)
dC: 126.4, 126.9, 127.3, 127.6, 128.2, 128.8, 129.0, 131.2, 131.5,
132.2, 133.6, 134.1, 134.6, 135.5, 140.5, 150.1, 152.3, 173.9,
179.7, 182.0. HRMS (positive ESI): m/z calcd for C25H12Cl2O4 +
Na+: 469.00103 (M+), 470.99808 (M + 2)+, 473.00479 (M +
4)+. Found: 469.00049, 470.99754, 472.99463. Anal. calcd for
C25H12Cl2O4: C, 67.13; H, 2.70%. Found: C, 67.05; H, 2.64%.
3-(4-Isopropylphenyl)-2-(2-naphthylcarbonyl)-4,9-dihydro-
naphtho[2,3-b]furane-4,9-dione (10m). Yellow solid; Yield: 78%
(MW), 70% (Thermal); m.p. 170–171 ◦C; IR (KBr): 1743, 1683,
1
1544, 1359, 1267 cm-1; H NMR (300 MHz, CDCl3) dH: 1.11
2-(4-Chlorobenzoyl)-3-(4-fluorophenyl)-4,9-dihydronaphtho-
[2,3-b]furane-4,9-dione (10i). Yellow solid; Yield: 79% (MW),
71% (Thermal); m.p. 221–222 ◦C; IR (KBr): 1684, 1643, 1531,
(d, 6H, J = 6.9, CH3), 2.80 (sep, 1H, J = 6.9, CH), 7.13 (d,
2H, J = 8.4, Ar–H), 7.41 (d, 2H, J = 8.1, Ar–H), 7.50 (t, 1H,
J = 7.5 Hz, Ar–H), 7.59 (t, 1H, J = 7.5, Ar–H), 7.79–7.84 (m,
5H, Ar–H), 7.90 (dd, 1H, J = 8.7, 1.5 Hz, Ar–H), 8.17–8.21 (m,
1H, Ar–H), 8.27–8.30 (m, 1H, Ar–H), 8.33 (s, 1H, Ar–H); 13C
NMR (75 MHz, CDCl3) dC: 23.6, 33.9, 124.7, 125.5, 126.0,
126.7, 126.9, 127.3, 127.7, 127.8, 128.4, 128.8, 129.7, 130.3,
132.0, 132.2, 132.4, 132.5, 133.0, 134.0, 134.4, 135.7, 149.9,
150.9, 152.7, 174.1, 180.1, 183.9. HRMS (positive ESI): m/z
calcd for C32H22O4 + Na+: 493.14158. Found: 493.14103. Anal.
calcd for C32H22O4: C, 81.69; H, 4.71%. Found: C, 81.62; H,
4.65%.
1
1351, 1224 cm-1; H NMR (300 MHz, CDCl3) dH: 7.10–7.17
(m, 2H, Ar–H), 7.43–7.47 (m, 2H, Ar–H), 7.49–7.55 (m, 2H,
Ar–H), 7.80–7.84 (m, 2H, Ar–H), 7.89–7.93 (m, 2H, Ar–H),
8.16–8.20 (m, 1H, Ar–H), 8.26–8.30 (m, 1H, Ar–H); 13C NMR
(75 MHz, CDCl3) dC: 115.6, 124.0, 127.0, 127.4, 127.7, 129.0,
131.3, 131.5, 132.2, 133.8, 134.2, 134.3, 134.6, 140.5, 150.2,
152.4, 163.3, 173.9, 179.8, 182.2. HRMS (positive ESI): m/z
calcd for C25H12ClFO4 + Na+: 453.03058 (M+), 455.02763 (M +
2)+. Found: 453.03004, 455.02709. Anal. calcd for C25H12ClFO4:
C, 69.70; H, 2.81%. Found: C, 69.63; H, 2.86%.
3-(4-Chlorophenyl)-2-(2-naphthylcarbonyl)-4,9-dihydronaph-
tho[2,3-b]furan-4,9-dione (10n). Yellow solid; Yield: 81%
(MW), 74% (Thermal); m.p. 203–204 ◦C; IR (KBr): 1741,
3-(4-Chlorophenyl)-2-(4-methylbenzoyl)-4,9-dihydro naphtho-
[2,3-b]furane-4,9-dione (10j). Yellow solid; Yield: 80% (MW),
75% (Thermal); m.p. 253–254 ◦C; IR (KBr): 1679, 1641, 1590,
1
1661, 1639, 1351, 1218 cm-1; H NMR (300 MHz, CDCl3) dH:
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7.35–7.38 (m, 2H, Ar–H), 7.48–7.53 (m, 2H, Ar–H), 7.55–
7.66 (m, 2H, Ar–H), 7.78–7.84 (m, 2H, Ar–H), 7.86–7.91 (m,
2H, Ar–H), 7.94–8.00 (m, 2H, Ar–H), 8.15–8.19 (m, 1H, Ar–
H), 8.24–8.30 (m, 1H, Ar–H), 8.50 (s, 1H, Ar–H); 13C NMR
(75 MHz, CDCl3) dC: 124.7, 126.8, 126.9, 127.0, 127.3, 127.7,
127.8, 128.2, 128.6, 129.1, 129.8, 130.7, 131.6, 132.3, 132.6,
133.1, 133.7, 134.1, 134.5, 135.3, 135.9, 150.9, 152.4, 173.9,
179.9, 183.3. HRMS (positive ESI): m/z calcd for C29H15ClO4 +
Na+: 485.05566 (M+), 487.05271 (M + 2)+. Found: 485.05511,
487.05216. Anal. calcd for C29H15ClO4: C, 75.25; H, 3.27%.
Found: C, 75.19; H, 3.33%.
41, 3107. Reformatsky reaction: (d) N. Azizi, L. Torkiyan and M. R.
Saidi, Org. Lett., 2006, 8, 2079. Tsuji–Trost reaction: (e) H. Kinoshita,
H. Shinokubo and K. Oshima, Org. Lett., 2004, 6, 4085. Barbier
reaction: (f) Z. Zha, A. Hui, Y. Zhou, Q. Miao, Z. Wang and H.
Zhang, Org. Lett., 2005, 7, 1903. Aldol reaction: (g) L. Botella and
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8 For selected recent examples, see: (a) K. Kumaravel and G. Vasuki,
Green Chem., 2009, 11, 1945; (b) N. Ma, B. Jiang, G. Zhang, S.-J. Tu,
W. We v e r a n d G. L i , Green Chem., 2010, 12, 1357; (c) Y. Zhou, Y.
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9 M. F. Sartori, Chem. Rev., 1963, 63, 279.
10 R. H. Thomson, Naturally Occurring Quinones, Chapman and Hall,
New York, 1997.
11 (a) D. G. I. Kingston and M. M. Rao, Planta Med., 1980, 39, 230;
(b) M. M. Rao and D. G. I. Kingston, J. Nat. Prod., 1982, 45,
600.
3-(3-Fluorophenyl)-2-(2-naphthylcarbonyl)-4,9-dihydronaph-
tho[2,3-b]furan-4,9-dione (10o). Yellow solid; Yield: 77%
(MW), 71% (Thermal); m.p. 179–180 ◦C; IR (KBr): 1670, 1661,
1639, 1359, 1267 cm-1;1H NMR (300 MHz, CDCl3) dH: 7.02–
7.08 (m, 1H, Ar–H), 7.30–7.34 (m, 3H, Ar–H), 7.56 (t, 1H,
J = 7.5, Ar–H), 7.64 (t, 1H, J = 7.5, Ar–H), 7.81–8.00 (m, 6H,
Ar–H), 8.18–8.21 (m, 1H, Ar–H), 8.28–8.31 (m, 1H, Ar–H),
8.48 (s, 1H, Ar–H); 13C NMR (75 MHz, CDCl3) dC: 116.4,
117.6, 117.9, 125.1, 126.4, 127.3, 127.7, 128.2, 129.0, 129.5,
129.8, 129.9, 130.2, 130.7, 130.9, 132.9, 133.5, 134.2, 134.5,
134.9, 136.3, 141.4, 152.8, 162.6, 174.3, 180.2, 183.7. HRMS
(positive ESI): m/z calcd for C29H15FO4 + Na+: 469.08521 (M+).
Found: 469.08466. Anal. calcd for C29H15FO4: C, 78.02; H,
3.39%. Found: C, 77.94; H, 3.33%.
12 (a) C. E. Heltzel, A. A. L. Gunatilaka, T. E. Glass and D. G. I.
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Acknowledgements
SP and JCM thank MICINN, Spain, and the Department
of Science and Technology, New Delhi, for funding for
Indo-Spanish collaborative major research projects (grants
DST/INT/SPAIN/09 and ACI2009-0956). SP and JCM also
gratefully acknowledge DST for funds under IRHPA program
for the purchase of a high resolution NMR spectrometer and
MICINN for grant CTQ2009-12320-BQU, respectively.
14 T. Takegami, E. Simamura, K.-I. Hirai and J. Koyama, Antiviral Res.,
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Notes and references
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3 V. K. Ahluwalia and R. S. Varma, Green Solvents for Organic
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22 T. Shu, D.-W. Chen and M. Ochiai, Tetrahedron Lett., 1996, 37, 5539.
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24 For representative recent examples, see: (a) H. M. Godbole, A. A.
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25 For general selected reviews and monographs of microwave-assisted
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4 For the first discussion of the concept of “on-water reactions” see:
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5 For a review of stereoselective reactions in water, see: U. M.
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7 For representative examples of the use of water as solvent in common
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Kakumoto, K. Manabe and S. Kobayashi, Tetrahedron Lett., 2000,
2128 | Green Chem., 2011, 13, 2123–2129
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26 For a review of the impact of microwaves in green chemistry, see:
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27 (a) M. J. Gronnow, R. J. White, J. H. Clark and D. J. Macquarrie,
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29 Two previous reports exist of the synthesis of dihydrofurans using
pyridinium ylides, involving (i) aromatic aldehydes and cyclohexane-
1,3-dione/dimedone/4-hydroxycoumarin which formed the Michael
acceptors, viz. a,b-unsaturated 1,3-diones and (ii) acyclic a,b-
unsaturated ketones/esters. All these reactions were performed in
organic solvents, namely acetonitrile or i-PrOH. See: (a) C. P. Chuang
and A. I. Tsai, Synthesis, 2006, 4, 675; (b) Q-F. Wang, H. Hou, Li.
Hui and C. G. Yan, J. Org. Chem., 2009, 74, 7403.
28 J. D. Moseley and C. O. Kappe, Green Chem., 2011, 13,
794.
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