Multicomponent reactions of furan-2,3-diones: Synthesis and characterizations of furo[3,2-c]pyran-4-ones

Article abstract of DOI:10.1002/hlca.200900374

Furo[3,2-c]pyran-4-ones, which possess a natural-product skeleton, are synthesized via a simple, onepot, three-component reaction of furan-2,3-diones with dialkyl acetylenedicarboxylates and Ph₃P.

Full text of DOI:10.1002/hlca.200900374

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Multicomponent Reactions of Furan-2,3-diones: Synthesis and
Characterizations of Furo[3,2-c]pyran-4-ones
a
b
c
˙
˙
by Irfan Koca* ), Ismail Yıldırım ), and Ertan S¸ahin )
a) Department of Chemistry, Faculty of Arts and Sciences, Bozok University, TR-66200 Yozgat
(phone: þ 903542421021; fax: þ 903542421022; e-mail: i_koca@yahoo.com)
b) Department of Chemistry, Faculty of Arts and Sciences, Erciyes University, TR-38039 Kayseri
c) Department of Chemistry, Faculty of Science, Atatꢀrk University, TR-25240 Erzurum
Furo[3,2-c]pyran-4-ones, which possess a natural-product skeleton, are synthesized via a simple, one-
pot, three-component reaction of furan-2,3-diones with dialkyl acetylenedicarboxylates and Ph3P.
Introduction. – Inoscavin A and phelligridin F, which possess a 2,3-dihydrofuro[3,2-
c]pyran-4-one skeleton, are natural products that were isolated from a fungus. There
are several reports about these compounds as free-radical scavengers with cytotoxic
activities [1 – 4]. Niveulone, which also contains a 2,3-dihydrofuro[3,2-c]pyran-4-one
moiety, which is linked to a more ꢁclassicalꢂ terpenoid part in a heterocyclic spiro-
compound, was isolated as one of several biologically active metabolites of the
ascomycete Dasyscyphus niveus. It is weakly cytotoxic towards human cell lines and has
an challenging structure with an interesting C-skeleton [5]. The phellifuropyranone, 2-
(3,4-dihydroxyphenyl)-6-[(E)-2-(3,4-dihydroxyphenyl)ethenyl]furo[3,2-c]pyran-4-one,
has antiproliferative activity against mouse melanoma cells and human lung cancer
cells in vitro [6].
Some 4H-pyran derivatives are potential bioactive compounds, such as calcium
antagonists [7] or potent apoptosis inducers [8][9]. Some 2-amino-4H-pyrans can be
employed as photoactive materials [10]. 4H-Benzo[b]pyrans and their derivatives have
attracted much interest due to their biological and pharmacological properties, such as
anticoagulant, spasmolytic, diuretic, anticancer, and antianaphylactin characteristics
[11][12]. Furthermore, the 4H-pyran group is a constituent of the structures of a series
of natural products [13 – 15].
Furan-2,3-diones 1a – 1d are versatile starting materials for a variety of reactions,
e.g., generation of diacyl ketenes by thermolysis, cycloaddition of heterocumulenes,
ꢃ 2010 Verlag Helvetica Chimica Acta AG, Zꢀrich

Helvetica Chimica Acta – Vol. 93 (2010)
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photochemical reactions, as well as additon of nucleophiles, leading to a number of
heterocyclic systems [16].
The development of simple synthetic routes for widely used organic compounds
from readily available reagents is one of the major tasks in organic synthesis. Nowadays,
the one-pot reactions involving multicomponent condensation are popular for the
synthesis of heterocyclic compounds [17]. They are more convenient than multistep
reactions, since they require shorter reaction time and give higher yields with easy
workup. Multicomponent reactions constitute an especially attractive synthetic
strategy, since they provide easy and rapid access to large libraries of organic
compounds with diverse substitution patterns. As multicomponent reactions are one-
pot reactions, they are easier to carry out than multistep syntheses [18][19].
An experimental as well as theoretical article for multicomponent reactions of
furan-2,3-diones has been published recently [20]. The aim of the present study was to
accomplish multicomponent reactions of 1a – 1d with dialkyl acetylenedicarboxylates
and Ph3P. Here, we report the reaction mechanism, synthesis, and characterization of
furo[3,2-c]pyran-4-one derivatives. Thus, compounds 3a – 3h have been first synthe-
sized by these reactions (Scheme 1), and the experimental and spectroscopic results are
discussed.
Results and Discussion. – The reaction of the acetylenedicarboxylates 2 with 1a – 1d
in the presence of Ph3P in benzene proceeded smoothly to afford the target compounds
3a – 3h in 33 – 51% yield. The structures of compounds 3a – 3h were determined by IR,
1H- and 13C-NMR spectra, and elemental analyses.
Due to the presence of three electrophilic sites with different reactivities (i.e., C(2),
C(3) and C(5)) in furandiones 1 that can react with nucleophiles [16][21][22], the
reactions of 1 with the phosphonium intermediate formed from Ph3P and 2 (acts as a
carbanion) may produce four different isomeric novel compounds 3 – 6 (Scheme 1).
However, TLC studies for each reaction indicated the presence of only one product, the
structure of which was identified as alkyl 2-alkoxy-7-aroyl-6-aryl-4-oxo-4H-furo[3,2-
c]pyran-3-carboxylate 3.
The IR spectra of 3a showed absorption bands at 1760, 1709, and 1649, and 1601 –
1472 cmꢀ1 due to three C¼O and aromatic bonds, respectively. The absorptions of
CꢀOꢀC groups were observed at 1259 cmꢀ1. The 1H-NMR spectrum of 3a exhibited
four sharp singlets for the MeO groups at d(H) 3.72, 3.80, 3.87, and 4.02. The signals of
1
aromatic H-atoms were observed as AA’BB’ system at d(H) 6.72 – 7.80 ppm. The H-
decoupled 13C-NMR spectrum of 3a showed 21 resonances, in good agreement with the
1
proposed structure (see Exper. Part). The H- and 13C-NMR spectra of 3b – 3h were
similar to those of 3a, except for the signals of the substituent at C(6), C(7), and the ester
moieties, which exhibited characteristic resonances with appropriate chemical shifts.
The structures of the products are based on an X-ray study of methyl 2-methoxy-7-
(4-methoxybenzoyl)-6-(4-methoxyphenyl)-4-oxo-4H-furo[3,2-c]pyran-3-carboxylate
(3a; Fig.) and methyl 2-methoxy-7-(4-methylbenzoyl)-6-(4-methylphenyl)-4-oxo-4H-
furo[3,2-c]pyran-3-carboxylate (3b) [20], thus excluding the other possible isomers. An
ORTEP representation of 3a is shown in the Figure.
The compound crystallizes in the monoclinic space group C2/c, and there is one
molecule in the asymmetric unit. The furo-pyran bicycle is not strictly planar; it is

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Helvetica Chimica Acta – Vol. 93 (2010)
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Figure. ORTEP Plot of 3a, with the atom-numbering scheme. Displacement ellipsoids are drawn at the
50% probability level, and the H-atoms are shown as small spheres of arbitrary radii.
considerably strained due to the substituted units. Maximum deviation from the mean
plane is 0.108 ꢄ for C(10).
A reasonable reaction pathway from furan-2,3-diones 1 to furo[3,2-c]pyran-4-one
derivatives 3 is outlined in Scheme 2. The first step may involve the addition of Ph3P to
the acetylenedicarboxylate 2 and formation of the zwitterionic 1:1 adduct. The
subsequent step is the nucleophilic attack of the adduct to the lactone C¼O group of 1.
Rearrangement of the intermediate (a betaine) thus formed may lead to pyrandione
derivatives 7. Next, an intramolecular Wittig reaction by elimination of Ph3P¼O yields
the intermediate 8, which would be transformed to the product 3 (see Scheme 2).
Scheme 2. Formation of Furo[3,2-c]pyran-4-ones

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On the other hand, we investigated the reaction of the furan-3-one derivatives of
type 9 [22] with 2a in the presence of Ph3P; but no reaction was observed (TLC control;
Scheme 3). These studies confirm that the reactions with furan-2,3-diones 1 are
initiated at the lactone group.
Scheme 3. Attempted Reaction Furan-3-ones with Dimethyl Acetylenedicarboxylates and Ph3P
Conclusions. – Multicomponent reactions with furan-2,3-diones 1 have been
reported here for the first time. We have developed a novel, one-pot, three-component
synthesis of furo[3,2-c]pyran-4-ones 3a – 3h. These functionalized products are
amenable to further transformations, and we anticipate that they may have important
applications in medicinal and synthetic organic chemistry.
Experimental Part
General. Compounds 1 were prepared according to [21][23]. Compound 2 and other reagents or
solvents were obtained from Merck, Fluka, and Sigma, and used without further purification. TLC:
Merck precoated silica gel 60 F 254. M.p.: Electrothermal 9200 apparatus; uncorrected. IR Spectra: Jasco
FT-IR-460 Plus spectrometer; in cmꢀ1. 1H- and 13C-NMR spectra: Bruker AC300 instrument, in CDCl3 at
300 and 75 MHz, resp.; d in ppm, J in Hz. Elemental analyses (C, H): LECO-932 CHNS-O analyzer. X-
Ray: Rigaku R-AXIS RAPID-S diffractometer.
General Procedure for the Preparation of Compounds 3a – 3h. To a stirred soln. of furan-2,3-diones 1
(1 mmol) and dialkyl acetylenedicarboxylates 2 (1 mmol) in benzene (20 ml) was added dropwise Ph3P
(1 mmol) in benzene (5 ml), and the mixture was stirred at r.t. for 10 min. Then, the mixture was heated
at reflux for 15 min. The solvent was removed under reduced pressure, and the residue was treated with
the proper alcohol to give the corresponding products 3, which were filtered off, recrystallized from the
proper alcohol or solvent and dried (P2O5).
Methyl
2-Methoxy-6-(4-methoxyphenyl)-7-[(4-methoxyphenyl)carbonyl]-4-oxo-4H-furo[3,2-
c]pyran-3-carboxylate (3a). From treatment with i-PrOH; recrystallized from PrOH. Yield: 0.17 g
(36%). Yellow crystals. M.p. 1768. IR (KBr): 1760, 1709, 1649 (C¼O), 1601, 1550, 1511, 1472 (C¼C),
1259 (CꢀO). 1H-NMR (300.13 MHz, CDCl3): 7.80 – 6.72 (2 AA’BB’, 8 arom. H); 4.02, 3.87, 3.80, 3.72 (4s,
4 MeO). 13C-NMR (75.47 MHz, CDCl3): 188.36 (t, 3J ¼ 4.3, ArꢀC¼O); 157.80 (s, C¼O, ester); 155.56 (s,
C¼O, lactone); 167.89, 164.51, 163.18, 161.65, 151.56, 132.16, 130.14, 129.30, 123.57, 114.12, 114.07, 107.45,
106.87, 89.08 (C¼C, arom., olef.); 59.34, 55.56, 55.32, 51.92 (4 MeO). Anal. calc. for C25H20O9 (464.42): C
64.65, H 4.34; found: C 64.75, H 4.25.
Methyl 2-Methoxy-6-(4-methylphenyl)-7-[(4-methylphenyl)carbonyl]-4-oxo-4H-furo[3,2-c]pyran-3-
carboxylate (3b). From treatment with MeOH; recrystallized from MeOH. Yield: 0.22 g (51%). Yellow
crystals. M.p. 168 – 1708. IR (KBr): 1766, 1714, 1655 (C¼O), 1604, 1570, 1510, 1475 (C¼C), 1230 (CꢀO).
1H-NMR (300.13 MHz, CDCl3): 7.80 – 7.09 (2 AA’BB’, 8 arom. H); 4.09, 3.96 (2s, 2 MeO); 2.42, 2.33 (2s,
2 MeꢀAr). 13C-NMR (75.47 MHz, CDCl3): 191.46 (t, 3J ¼ 4.4, ArꢀC¼O); 160.28 (s, C¼O, ester); 157.49
(s, C¼O, lactone); 165.22, 163.63, 153.27, 147.54, 143.50, 135.86, 131.82, 131.57, 131.33, 130.38, 130.28,
121.29, 109.85, 89.60 (C¼C, arom., olef.); 61.30, 53.95 (2 MeO); 23.78, 23.41 (2 MeꢀAr). Anal. calc. for
C25H20O7 (432.42): C 69.44, H 4.66; found: C 69.56, H 4.79.

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Methyl 6-(3,4-Dimethoxyphenyl)-7-[(3,4-dimethoxyphenyl)carbonyl]-2-methoxy-4-oxo-4H-fu-
ro[3,2-c]pyran-3-carboxylate (3c). From treatment with MeOH; recrystallized from MeOH. Yield:
0.24 g (46%). Yellow crystals. M.p. 1308. IR (KBr): 1767, 1713, 1646 (C¼O), 1611, 1581, 1514, 1468
(C¼C), 1265 (CꢀO). 1H-NMR (300.13 MHz, CDCl3): 7.50 – 6.72 (m, 6 arom. H); 4.10, 3.92, 3.91, 3.90,
3
3.84, 3.78 (6s, 6 MeO). 13C-NMR (75.47 MHz, CDCl3): 188.48 (t, J ¼ 4.2, ArꢀC¼O); 155.63 (s, C¼O,
ester); 154.49 (s, C¼O, lactone); 163.22, 157.50, 155.63, 151.56, 151.28, 149.34, 148.80, 129.26, 125.61,
123.71, 122.15, 110.83, 110.74, 110.50, 110.17, 107.60, 106.87, 89.01 (C¼C, arom., olef.); 59.42, 56.18, 56.03,
55.91, 53.67, 52.02 (6 MeO). Anal. calc. for C27H24O4 (524.13): C 61.83, H 4.61; found: C 61.58, H, 4.76.
7-Ethyl 3-Methyl 6-Ethoxy-2-methoxy-4-oxo-4H-furo[3,2-c]pyran-3,7-dicarboxylate (3d). From
treatment with MeOH; recrystallized from MeOH. Yield: 0.17 g (45%). Yellow crystals. M.p. 1478. IR
(KBr): 1771, 1715 (C¼O), 1614, 1577, 1553, 1473 (C¼C), 1246 (CꢀO). 1H-NMR (300.13 MHz, CDCl3):
3
3
7.56 – 7.24 (m, 5 arom. H); 4.23 (s, MeO); 4.22 (q, J ¼ 7.1, CH2O); 3.88 (s, MeO); 1.12 (t, J ¼ 7.1, Me ) .
13C-NMR (75.47 MHz, CDCl3): 162.43 (s, C¼O, ethyl ester); 161.63 (s, C¼O, methyl ester); 161.59 (s,
C¼O, lactone); 163.34, 154.97, 150.34, 131.66, 130.07, 128.66, 128.34, 108.16, 102.86, 88.90 (C¼C, arom.,
olef.); 62.02 (CH2O); 59.40, 52.02 (2 MeO); 13.72 (Me). Anal. calc. for C19H16O8 (372.33): C 61.29, H
4.66; found: C 61.01, H 4.48.
Ethyl 2-Ethoxy-6-(4-methoxyphenyl)-7-[(4-methoxyphenyl)carbonyl]-4-oxo-4H-furo[3,2-c]pyran-3-
carboxylate (3e). From treatment with EtOH; recrystallized from MeOH. Yield: 0.25 g (51%). Yellow
crystals. M.p. 1208. IR (KBr): 1765, 1709, 1645 (C¼O), 1607, 1553, 1509, 1467 (C¼C), 1259 (CꢀO).
1H-NMR (300.13 MHz, CDCl3): 7.77 – 6.71 (2 AA’BB’, 8 arom. H); 4.33 (q, 3J ¼ 7.1, CH2O); 4.31 (q, 3J ¼
3
3
7.1, CH2O); 3.78, 3.70 (2s, 2 MeO); 1.34 (t, J ¼ 7.1, Me); 1.32 (t, J ¼ 7.1, Me ) . 13C-NMR (75.47 MHz,
CDCl3): 188.49 (t, 3J ¼ 4.3, ArꢀC¼O); 161.33 (s, C¼O, ester); 157.67 (s, C¼O, lactone); 164.50, 162.80,
161.57, 155.65, 151.64, 132.18, 130.07, 129.29, 123.57, 114.12, 114.04, 107.32, 106.93, 90.05 (C¼C, arom.,
olef.); 69.75, 60.85 (2 CH2O); 55.60, 55.33 (2 MeO); 14.74, 14.21 (Me). Anal. calc. for C27H24O9 (492.14):
C 65.85, H 4.91; found: C 65.50, H 4.78.
Ethyl 2-Ethoxy-6-(4-methylphenyl)-7-[(4-methylphenyl)carbonyl]-4-oxo-4H-furo[3,2-c]pyran-3-
carboxylate (3f). From treatment with MeOH; recrystallized from DMF/H2O (4 :1). Yield: 0.15 g
(33%). Yellow crystals. M.p. 1368. IR (KBr): 1762, 1717, 1665 (C¼O), 1606, 1572, 1554, 1442 (C¼C),
1234 (CꢀO). 1H-NMR (300.13 MHz, CDCl3): 7.73 – 7.03 (2 AA’BB’, 8 arom. H), 4.37 (q, 3J ¼ 7.1, CH2O);
3
3
3
4.35 (q, J ¼ 7.1, CH2O); 2.35, 2.26 (2s, 2 MeꢀAr); 1.39 (t, J ¼ 7.1, Me); 1.35 (t, J ¼ 7.1, Me ) . 13C-NMR
3
(75.47 MHz, CDCl3): 189.58 (t, J ¼ 4.5, ArꢀC¼O); 158.14 (s, C¼O, ester); 155.55 (s, C¼O, lactone);
162.86, 161.30, 151.34, 145.49, 141.42, 133.95, 129.80, 129.55, 129.32, 128.33, 107.74, 107.62, 90.18 (C¼C,
arom., olef.); 69.76, 60.89 (2 CH2O); 21.77, 21.40 (2 MeꢀAr); 14.70, 14.19 (Me). Anal. calc. for C27H24O7
(460.48): C 70.42, H 5.25; found: C 70.72, H 5.44.
Ethyl 6-(3,4-Dimethoxyphenyl)-7-[(3,4-dimethoxyphenyl)carbonyl]-2-ethoxy-4-oxo-4H-furo[3,2-
c]pyran-3-carboxylate (3g). From treatment with MeOH; recrystallized from MeOH. Yield: 0.27 g
(49%). Yellow crystals. M.p. 1448. IR (KBr): 1766, 1721, 1655 (C¼O), 1610, 1579, 1513, 1462 (C¼C),
1261 (CꢀO). 1H-NMR (300.13 MHz, CDCl3): 7.45 – 6.66 (m, 6 arom. H); 4.35 (q, 3J ¼ 7.1, CH2O); 4.32
(q, 3J ¼ 7.1, CH2O); 3.86, 3.84, 3.78, 3.72 (4s, 4 MeO); 1.35 (t, 3J ¼ 7.1, 2 Me ) . 13C-NMR (75.47 MHz,
CDCl3): 188.56 (t, 3J ¼ 4.4, ArꢀC¼O); 155.64 (s, C¼O, ester); 154.46 (s, C¼O, lactone); 162.85, 161.31,
157.35, 151.63, 151.22, 149.33, 148.79, 129.34, 125.58, 123.77, 122.05, 110.79, 110.50, 107.46, 106.94, 90.17
(C¼C, arom., olef.); 69.84, 60.90 (CH2O); 56.17, 56.02, 55.88 (MeO); 14.75, 14.20 (s, Me). Anal. calc. for
C29H28O10 (552.53): C 63.04, H 5.11; found: C 62.88, H 5.21.
Diethyl 2,6-Diethoxy-4-oxo-4H-furo[3,2-c]pyran-3,7-dicarboxylate (3h). From treatment with i-
PrOH; recrystallized from EtOH. Yield: 0.20 g (50%). Yellow crystals. M.p. 1268. IR (KBr): 1759, 1727,
1
1707 (C¼O), 1610, 1594, 1549, 1478 (C¼C), 1241 (CꢀO). H-NMR (300.13 MHz, CDCl3): 7.53 – 7.34
(m, 5 arom. H); 4.53 (q, 3J ¼ 7.1, CH2O); 4.30 (q, 3J ¼ 7.1, CH2O); 4.18 (q, 3J ¼ 7.1, CH2O); 1.46 (t, 3J ¼ 7.1,
Me); 1.32 (t, 3J ¼ 7.1, Me); 1.07 (t, 3J ¼ 7.1, Me ) . 13C-NMR (75.47 MHz, CDCl3): 162.44 (s, C¼O, ester at
C(7)); 161.41 (s, C¼O, ester at C(3)); 161.17 (s, C¼O, lactone); 162.95, 154.95, 150.40, 131.69, 130.97,
128.58, 128.29, 108.02, 102.88, 89.93 (C¼C, arom., olef.); 69.81, 61.97, 60.84 (3 CH2O); 14.88, 14.18, 13.68
(Me). Anal. calc. for C21H20O8 (400.38): C 63.00, H 5.03; found: C 62.80, H 5.09.
X-Ray Crystallography. For the crystal structure determination, the single-crystal of 3a was used for
data collection at r.t. on a four-circle Rigaku R-AXIS RAPID-S diffractometer (equipped with a two-

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Helvetica Chimica Acta – Vol. 93 (2010)
dimensional area IP detector). The graphite-monochromatized MoKa radiation (l 0.71073 ꢄ) and
oscillation-scan technique with Dw ¼ 58 for one image were used for data collection. The lattice
parameters were determined by the least-squares methods on the basis of all reflections with F2 > 2s(F2).
Integration of the intensities, correction for Lorentz and polarization effects, and cell refinement was
performed using CrystalClear (Rigaku/MSC Inc., 2005) software [24]. The structures were solved by
direct methods using SHELXS-97 [25] and refined by a full-matrix least-squares procedure using the
program SHELXL-97 [25]. The H-atoms were positioned geometrically and refined using a riding model.
The final difference Fourier maps showed no peaks of chemical significance.
Crystal Data of 3a. C25H20O9, crystal system, space group: monoclinic, C2/c; unit-cell dimensions:
a ¼ 25.3362(6), b ¼ 10.2945(2), c ¼ 17.5770(4) ꢄ, b ¼ 105.231(1)8; V: 4423.46(17) ꢄ3; Z ¼ 8; calculated
density: 1.39 mg/m3; absorption coefficient: 0.107 mmꢀ1; F(000): 1936; q range for data collection 2.2 –
26.48; refinement method: full-matrix least-squares on F2; data/parameters: 4519/311; goodness-of-fit
on F2: 1.051; final R indices [I > 2s(I)]: R1 ¼ 0.062, wR2 ¼ 0.128; R indices (all data): R1 ¼ 0.118, wR2 ¼
0.152; largest diff. peak and hole: 0.237 and ꢀ 0.199 e ꢄꢀ3. Crystallographic data were deposited with
CSD under CCDC registration number 732134. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif.
We wish to dedicate this article to Prof. Dr. Yunus AkÅamur, who passed away in 2007. This study was
financially supported by the Research Center of Erciyes University, project No.: EU-FBT-05/40.
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