Expeditious entry to novel 2-methylene-2,3-dihydrofuro[3,2-c] chromen-2-ones from 6-chloro-4-hydroxychromen-2-one and propargylic alcohols

Article abstract of DOI:10.3390/molecules16086470

A catalytic system consisting of the ruthenium(II) complex [Ru(σ³-2- C₃H₄Me)(CO)(dppf)][SbF ₆] (dppf = 1,1'-bis(diphenylphosphino)ferrocene) and trifluoroacetic acid has been used to promote the coupling of seco

Full text of DOI:10.3390/molecules16086470

Molecules 2011, 16, 6470-6480; doi:10.3390/molecules16086470
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Expeditious Entry to Novel 2-Methylene-2,3-dihydrofuro[3,2-c]
chromen-2-ones from 6-Chloro-4-hydroxychromen-2-one and
Propargylic Alcohols
Noel Nebra, Alba E. Díaz-Álvarez, Josefina Díez and Victorio Cadierno *
Departamento de Química Orgánica e Inorgánica, IUQOEM-CSIC, Facultad de Química, Universidad
de Oviedo, E-33071 Oviedo, Spain
* Author to whom correspondence should be addressed; E-Mail: vcm@uniovi.es;
Tel.: +34-985-103-453; Fax: +34-985-103-446.
Received: 14 July 2011; in revised form: 27 July 2011 / Accepted: 28 July 2011 /
Published: 2 August 2011
Abstract: A catalytic system consisting of the ruthenium(II) complex [Ru(η3-2-
C3H4Me)(CO)(dppf)][SbF6] (dppf = 1,1’-bis(diphenylphosphino)ferrocene) and trifluoroacetic
acid has been used to promote the coupling of secondary propargylic alcohols with
6-chloro-4-hydroxychromen-2-one. The reactions afforded unusual 2-methylene-2,3-
dihydrofuro[3,2-c]chromen-2-ones in good yields.
Keywords: chromen-2-ones; furochromen-2-ones; propargylic alcohols; ruthenium catalysts;
propargylation; cycloisomerization
1. Introduction
Chromen-2-ones (coumarins) constitute an important family of heterocyclic compounds of natural
origin which have attracted considerable attention for many years due to their versatile applications [1-4].
Among them, furochromen-2-ones (furocoumarins), tricyclic systems in which a furan ring is fused to
the chromen-2-one unit, are of particular interest since they exhibit potent biological and
pharmacological activity [5-8]. Although several methods of synthesis are presently known [7,8], new
approaches for the rapid and selective construction of furochromen-2-one scaffolds are still highly
desirable. In this context, recent efforts by different groups have been focused in the one-pot synthesis
of furo[3,2-c]chromen-2-ones (Figure 1) from readily available starting materials, with successful examples

Molecules 2011, 16
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including CAN-mediated cycloaddition of 4-hydroxychromen-2-one with terminal alkynes [9,10],
rhodium(II)-catalyzed heterocyclization of 3-diazo-2,4-chromenediones with terminal alkynes [11,12],
cascade addition/cyclization/oxidation of 3-alkynyl-chromones [13,14], Sonogashira-acetylide coupling/
demethylation/cyclization of 3-iodo-4-methoxychromen-2-ones [15,16] and alkynylation/
hydroalkoxylation of 3-bromo-4-acetoxychromen-2-ones [17].
Figure 1. The furo[3,2-c]chromen-2-one skeleton.
O
O
O
In the course of our studies focused on the application of ruthenium catalysts for the construction
of furan- and pyrrole-ring frameworks [18-25], we disclosed a straightforward approach of tetra-
substituted furans from readily accessible secondary propargylic alcohols and 1,3-dicarbonyl
compounds (Scheme 1) [18]. The process, which proceeds in a one-pot manner, involves the initial
trifluoroacetic acid-promoted propargylation of the 1,3-dicarbonyl compound, and subsequent
cycloisomerization of the resulting γ-ketoalkyne A (5-exo cyclization + aromatization) catalyzed by the
16-electron allyl-ruthenium(II) complex [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6] (1).
Scheme 1. Direct synthesis of furans from alkynols and 1,3-dicarbonyl compounds.
R1
1 (5 mol%)
R3
R4
O
O
O
HO
R2
CF CO H (50 mol%)
3
2
R1
+
H2O
+
R4
75 ºC
R3
R2
O
R3
propargylic
substitution
O
O
cycloisomerization
R4
R1
R2
H2O
(A)
PPh2
PPh2
SbF6
P
P P =
Fe
Ru
OC
P
(1)
By applying this synthetic route a large variety of furans containing carbonyl functionalities on the
aromatic ring, could be prepared in good yields starting from both terminal and internal secondary
alkynols, and β-diketones or β-keto esters [18,21]. In addition, we also demonstrated that furo[3,2-
c]chromen-2-ones are also accessible by this route using 4-hydroxychromen-2-one as substrate,
representing an appealing one-pot method of synthesis for this type of heterocycles [21]. Related work
by Zhou and co-workers also confirmed the utility of this propargylation-cycloisomerization sequence
for the construction of furochromen-2-one skeletons [26].

Molecules 2011, 16
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Following with these studies, herein we would like to communicate that related C–C coupling
processes involving 6-chloro-4-hydroxychromen-2-one and terminal propargylic alcohols
HC≡CC(OH)HR result in the selective formation of the 2-methylene-2,3-dihydrofuro[3,2-c]chromen-
2-one derivatives 4 (Figure 2), instead of the expected 8-chloro-substituted furo[3,2-c]chromen-2-ones
5, due to the reluctance of the former to undergo aromatization of the five-membered ring.
Figure 2. Structures of compounds 4 and 5.
O
O
Cl
R
R
Cl
O
O
O
O
(4)
(5)
2. Results and Discussion
Initially, the coupling of the secondary propargylic alcohol 1-(4-methoxyphenyl)-2-propyn-1-ol
(2a) with 6-chloro-4-hydroxychromen-2-one (3) was investigated under the same reaction conditions
previously employed by us in the synthesis of furo[3,2-c]chromen-2-one derivatives starting from
4-hydroxychromen-2-one [21], that is, heating a THF solution of both reactants (equimolar mixture) at
75 °C in the presence of 50 mol% of trifluoroacetic acid and 5 mol% of the allyl-ruthenium(II)
complex 1 (Scheme 2). Almost complete disappearance of the starting materials, accompanied by the
selective formation of a single reaction product 4a, was observed by GC after 8 hours of heating.
Scheme 2. Catalytic synthesis of compound 4a under classical thermal conditions.
OH
O
MeO
1 (5 mol%)
(2a)
Cl
CF CO H (50 mol%)
OMe
3
2
+
+ H2O
THF / 75 ºC / 8 h
(83% yield)
O
OH
O
Cl
(4a)
O
O
(3)
Appropriate chromatographic workup allowed the isolation of 4a as a crystalline yellow solid in
83% yield. NMR spectroscopic data obtained for 4a clearly revealed the selective formation of a
2-methylene-2,3-dihydrofuran unit, instead of the expected aromatic 2-methylfuran one (details are
given in the Experimental), a fact that was unambiguously confirmed by means of a single-crystal
X-ray diffraction study (an ORTEP view of the molecule is shown in Figure 3; selected bonding
parameters are listed in Table 2). The bond distance C10-C11 (1.321(3) Å) showed the expected value
for a C=C bond, while that observed for C10-C12 (1.523(3) Å) falls within the expected range for a
C(sp2)-C(sp3) single bond.

Molecules 2011, 16
Figure 3. ORTEP-type view of the structure of compound 4a showing the crystallographic
6473
labelling scheme. Thermal ellipsoids are drawn at the 20% probability level.
Table 2. Selected bond distances (Å) and angles (°) for compound 4a.
Distances
C8-C9
C9-O3
1.338(3)
1.360(2)
1.417(2)
1.321(3)
1.523(3)
1.507(3)
1.393(3)
1.211(3)
1.738(2)
O3-C10
C10-C11
C10-C12
C12-C8
C7-O1
C7-O2
C1-Cl1
Angles
C8-C9-O3
114.13(18)
106.39(16)
118.8(2)
C9-O3-C10
O3-C10-C11
C11-C10-C12
O3-C10-C12
C10-C12-C8
C12-C8-C9
131.1(2)
110.07(16)
99.46(17)
109.77(18)
The use of microwave (MW) irradiation represents a convenient alternative to the conventional
thermal heating in organic synthesis since a more effective energy transfer to the system takes place,
thus shortening considerably the reaction times and improving in many cases the product yields [27-29].
Accordingly, we have found that, performing the same coupling reaction of alkynol 2a with 3 under
controlled microwave heating at 75 °C, selective and almost quantitative formation of 2-methylene-
2,3-dihydrofuro[3,2-c]chromen-2-one (4a, 99% GC-yield; 89% isolated yield) takes place after only
10 min. As shown in Scheme 3, the process is general since the related heterocycles 4b–d could also
be synthesized in good yields (77%–92%) by reacting 3 with the secondary propargylic alcohols 1-(2-
methoxyphenyl)-2-propyn-1-ol (2b), 1-(1-naphthyl)-2-propyn-1-ol (2c) and 1-(2-thienyl)-2-propyn-1-
ol (2d) under the same MW conditions.

Molecules 2011, 16
Scheme 3. Catalytic synthesis of compound 4a–d under MW-irradiation.
6474
OH
R
O
1 (5 mol%)
CF CO H (50 mol%)
R
Cl
(2a-d)
3
2
+
+ H2O
THF / MW (300 W) / 75 ºC / 10 min
(77-92% yield)
OH
O
O
Cl
(4a-d)
R = 4-C6H4OMe (a), 2-C6H4OMe (b), 1-Naphthyl (c), 2-Thienyl (d)
O
O
(3)
The presence of a 2-methylene-2,3-dihydrofuran moiety in the structure of these compounds was
readily identified by the appearance of a high-field CH carbon resonance at 43–49 ppm (CHR unit)
and a CH2 signal at ca. 92 ppm, typical of a terminal olefinic =CH2 unit, in their 13C{1H}-NMR spectra
(DEPT experiments). Characteristic 1H-NMR peaks for these units were also observed at 4.5–5.5 ppm
(details can be found in the Experimental).
At this point, it is worthy of note that occurrence of 2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-
ones has been scarcely documented in the literature [30-35], with most of the know examples being
disubstituted at the C-3 position of the 2-methylene-2,3-dihydrofuran ring which prevents their
tautomerization into the corresponding 2-methyl-furo[3,2-c]chromen-2-ones. In this sense, the
reluctance shown by compounds 4a–d to aromatize under the acidic conditions employed merits to be
highlighted. In fact, only in the case of 4b such aromatization process could be observed after
prolonged MW irradiation (3 h) of the reaction mixture at 100 °C. Under this conditions, the novel
8-chloro-substituted furo[3,2-c]chromen-2-one 5b could be synthesized with an acceptable 63% yield
and fully characterized (Scheme 4).
Scheme 4. Synthesis of the furo[3,2-c]chromen-2-one 5b.
OMe
OH
Me
O
O
1 (5 mol%)
CF CO H (50 mol%)
(2b)
3
2
Cl
+
+ H2O
THF / MW (300 W) / 100 ºC / 3 h
(63% yield)
OH
O
O
Cl
(5b)
O
O
(3)
Me
O
O
Cl
O
O
(4b)

Molecules 2011, 16
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3. Experimental
3.1. General
Solvents were dried by standard methods and distilled under nitrogen before use. The complex
[Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6] (1) [36] and propargylic alcohols 2a–d [37] were prepared by
following the methods reported in the literature. Flash chromatography was performed using Merck
silica gel 60 (230–400 mesh). Melting points were determined in a Gallenkamp apparatus and are
uncorrected. Infrared spectra were recorded on a Perkin-Elmer 1720-XFT spectrometer. NMR spectra
were recorded on a Bruker DPX-300 instrument at 300 MHz (1H) or 75.4 MHz (13C). The chemical
shift values (δ) are given in parts per million and are referred to the residual peak of the deuterated
solvent used (CDCl3). High-resolution mass spectra (HRMS) were provided by the Mass Spectrometry
Service of the Instituto de Investigaciones Químicas (IIQ-CSIC, Seville). CCDC 831021 contains the
supplementary crystallographic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
3.2. Synthesis of the 8-chloro-2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-ones 4a–d
Under a nitrogen atmosphere, a pressure-resistant septum-sealed glass vial was charged with the
corresponding propargylic alcohol 2a–d (1 mmol), 6-chloro-4-hydroxychromen-2-one (3) (0.197 g,
1 mmol), THF (0.5 mL), [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6] (1) (0.049 g, 0.05 mmol), CF3CO2H
(37 µL, 0.5 mmol) and a magnetic stirring bar. The vial was then placed inside the cavity of a CEM
Discover® S-Class microwave synthesizer and power was held at 300 W until the desired temperature
was reached (75 °C). Microwave power was automatically regulated for the remainder of the
experiment (10 min) to maintain the temperature (monitored by a built-in infrared sensor). Then, the
vial was cooled to room temperature, the volatiles removed under vacuum, and the residue purified by
flash chromatography (silica gel) using a mixture EtOAc/hexanes (1:20) as eluent. Characterization
data for the novel 8-chloro-2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-ones 4a–d are as follows:
8-Chloro-3-(4-methoxyphenyl)-2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-one (4a). Yellow solid
1
(0.303 g, 89%); m.p. 125–127 °C; IR (Nujol) ν = 1721 (C=O) cm−1; H-NMR (CDCl3) δ = 3.78 (s,
3H), 4.52 (dd, 1H, J = 3.4 and 2.8 Hz), 5.11 (m, 2H), 6.87 (d, 2H, J = 8.5 Hz), 7.23 (d, 2H, J = 8.5 Hz),
13
7.32 (d, 1H, J = 8.8 Hz), 7.53 (dd, 1H, J = 8.8 and 2.2 Hz), 7.75 (d, 1H, J = 2.2 Hz) ppm; C-NMR
(CDCl3) δ = 47.7, 55.2, 91.7, 107.4, 112.5, 114.2, 118.5, 122.2, 128.8, 129.6, 131.2, 132.7, 153.5,
159.1, 157.8, 162.9, 164.8 ppm; HRMS (EI) m/z = 340.0501, C19H13O4Cl requires 340.0502.
8-Chloro-3-(2-methoxyphenyl)-2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-one (4b). Yellow solid
(0.262 g, 77%); m.p. 122–124 °C; IR (Nujol) ν = 1748 (C=O) cm−1; 1H-NMR (CDCl3) δ = 3.79 (s, 3H),
4.55 (dd, 1H, J = 3.0 and 2.5 Hz), 5.12 (m, 2H), 6.82–6.91 (m, 3H), 7.25 (m, 1H), 7.34 (d, 1H, J = 8.9 Hz),
13
7.55 (dd, 1H, J = 8.9 and 2.4 Hz), 7.76 (d, 1H, J = 2.2 Hz) ppm; C-NMR (CDCl3) δ = 48.5, 55.3,
92.1, 107.2, 112.6, 113.0, 113.8, 118.6, 120.1, 122.3, 129.8, 130.0, 132.9, 140.7, 153.6, 157.9, 160.0,
163.4, 164.3 ppm; HRMS (EI) m/z = 340.0513, C19H13O4Cl requires 340.0502.

Molecules 2011, 16
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8-Chloro-3-(1-naphthyl)-2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-one (4c). Yellow solid (0.331 g,
92%); m.p. 140–142 °C; IR (Nujol) ν = 1719 (C=O) cm−1; 1H-NMR (CDCl3) δ = 4.55 (dd, 1H, J = 3.3
and 2.5 Hz), 5.15 (dd, 1H, J = 3.3 and 2.5 Hz), 5.33 (dd, 1H, J = 3.3 and 3.3 Hz), 7.33–7.49 (m, 5H),
13
7.81–7.85 (m, 5H) ppm; C-NMR (CDCl3) δ = 48.8, 92.3, 107.3, 112.6, 118.7, 122.4, 125.3, 126.2,
126.4, 127.0, 127.7, 127.9, 129.0, 129.8, 132.9, 133.0, 133.4, 136.5, 153.6, 157.9, 163.4, 164.5 ppm;
HRMS (EI) m/z = 360.0557, C22H13O3Cl requires 360.0553.
8-Chloro-3-(2-thienyl)-2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-one (4d). Orange solid (0.253 g,
80%); m.p. 131–133 °C; IR (Nujol) ν = 1733 (C=O) cm−1; 1H-NMR (CDCl3) δ = 4.72 (dd, 1H, J = 3.5
and 2.4 Hz), 5.18 (dd, 1H, J = 3.5 and 2.7 Hz), 5.48 (dd, 1H, J = 2.7 and 2.4 Hz), 6.98 (dd, 1H, J = 5.2
and 3.6 Hz), 7.12 (dd, 1H, J = 3.6 and 1.1 Hz), 7.25 (dd, 1H, J = 5.2 and 1.1 Hz), 7.35 (d, 1H, J = 9.0 Hz),
13
7.56 (dd, 1H, J = 9.0 and 2.5 Hz), 7.75 (d, 1H, J = 2.5 Hz) ppm; C-NMR (CDCl3) δ = 43.0, 92.3,
106.3, 112.1, 118.2, 122.0, 124.9, 125.6, 126.7, 129.4, 132.7, 141.2, 153.1, 157.3, 162.9, 163.0 ppm;
HRMS (EI) m/z = 315.9971, C16H9O3ClS requires 315.9961.
3.3. Synthesis of 8-chloro-3-(2-methoxyphenyl)-2-methyl-furo[3,2-c]chromen-2-one (5b)
Under nitrogen atmosphere, a pressure-resistant septum-sealed glass vial was charged with 1-(2-
methoxyphenyl)-2-propyn-1-ol (2b, 0.162 g, 1 mmol), 6-chloro-4-hydroxychromen-2-one (3, 0.197 g,
1 mmol), THF (0.5 mL), [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6] (1, 0.049 g, 0.05 mmol), CF3CO2H
(37 µL, 0.5 mmol) and a magnetic stirring bar. The vial was then placed inside the cavity of a CEM
Discover® S-Class microwave synthesizer and power was held at 300 W until the desired temperature
was reached (100 °C). Microwave power was automatically regulated for the remainder of the
experiment (3 h) to maintain the temperature (monitored by a built-in infrared sensor). Then, the vial
was cooled to room temperature, the volatiles removed under vacuum, and the residue purified by flash
chromatography (silica gel) using a mixture EtOAc/hexanes (1:20) as eluent to give 5b. Yellow solid
1
(0.214 g, 63%); m.p. 120–122 °C; IR (Nujol) ν = 1749 (C=O) cm−1; H-NMR (CDCl3) δ = 2.42
(s, 3H), 3.82 (s, 3H), 7.01–7.08 (m, 2H), 7.26–7.43 (m, 4H), 7.85 (d, 1H, J = 2.5 Hz) ppm; 13C-NMR
(CDCl3) δ = 12.1, 55.1, 110.6, 113.7, 116.2, 118.0, 118.3, 119.6, 120.0, 129.2, 129.4, 131.0, 132.9,
136.5, 150.1, 152.5, 156.9, 162.5, 163.0 ppm; HRMS (EI) m/z = 340.0496, C19H13O4Cl requires
340.0502.
3.4. X-ray Crystal Structure Determination of Compound 4a
The most relevant crystal and refinement data are collected in Table 1. Data collection was
performed on a Oxford Diffraction Xcalibur Nova single crystal diffractometer, using Cu-Kα radiation.
Images were collected at a 65 mm fixed crystal-to-detector distance using the oscillation method, with
1° oscillation and a 5 s exposure time per image. Data collection strategy was calculated with the
program CrysAlis Pro CCD [38]. Data reduction and cell refinement were performed with the program
CrysAlis Pro RED [38]. An empirical absorption correction was applied using the SCALE3
ABSPACK algorithm as implemented in the program CrysAlis Pro RED [38]. The software package
WinGX was used for space group determination, structure solution and refinement [39]. The structure
was solved by direct methods using SIR92 [40]. Isotropic least-squares refinement on F2 using

Molecules 2011, 16
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SHELXL97 was performed [41]. During the final stages of the refinements, all the positional
parameters and the anisotropic temperature factors of all the non-H atoms were refined. The
coordinates of the H atoms were found from different Fourier maps and included in a refinement with
2
2
2
2
isotropic parameters. The function minimized was [ΣwF − F )/Σw(F )]1/2 where w = 1/[σ2(F ) +
o
c
o
o
(aP)2 + bP] (a = 0.0902; b = 0.0000) with σ2(F ) from counting statistics and P = (Max (F
2F )/3. Atomic scattering factors were taken from the International Tables for X-ray Crystallography [42].
+
o
2
2
o
2
c
The crystallographic plot was made with PLATON [43].
Table 1. Crystal data and structure refinement parameters for compound 4a.
Empirical formula
Formula weight
C19H13O4Cl
340.74
Temperature
150(2) K
Wavelength
1.5418 Å
Crystal system, space group
Unit cell dimensions
triclinic, P-1
a = 4.8366(2) Å α = 94.822(4)°
b = 11.0016(5) Å β = 90.363(4)°
c = 14.6466(7) Å γ = 94.200(4)°
774.45(6) Å3
Volume
Z, calculated density
Absorption coefficient
F(000)
2, 1.461 mg/m3
2.369 mm−1
352
Crystal size
Theta range for data collection
Limiting indices
Reflections collected / unique
Completeness to theta = 73.76º
Refinement method
Data / restrains / parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R indices (all data)
0.37 × 0.03 × 0.02 mm
3.03 to 73.76°
−4 ≤ h ≤ 6, −13 ≤ k ≤ 12, −17 ≤ l ≤ 17
7403/2919 (Rint = 0.0214)
93.4%
Full-matrix least-squares on F2
2919/0/269
1.166
R1 = 0.0411, wR2 = 0.1177
R1 = 0.0517, wR2 = 0.1354
0.334 and −0.267 e·Å3
Largest diff. peak and hole
4. Conclusions
In summary, an efficient synthesis of unusual and remarkably stable 2-methylene-2,3-
dihydrofuro[3,2-c]chromen-2-one derivatives, by coupling of secondary propargylic alcohols with
commercially available 6-chloro-4-hydroxychromen-2-one, has been developed with the aid of the
catalytic system [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6]/CF3CO2H. Apparently, the presence of the
electron-withdrawing Cl substituent on the 4-hydroxychromen-2-one skeleton exerts a marked
influence on the behavior of these species since, as previously described by us [21], the same reactions
performed with its non-substituted counterpart leads to the selective formation of isomeric furo[3,2-
c]chromen-2-ones by aromatization of the five-membered ring. Overall, the results reported herein

Molecules 2011, 16
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represent a new example of the utility of the allyl-ruthenium(II) complex 1 in synthetic organic
chemistry [25].
Acknowledgments
This work was supported by the Spanish MICINN (Projects CTQ2006-08485/BQU, CSD2007-
00006 and CTQ2010-14796/BQU). N.N. thanks MEC of Spain and the European Social Fund (FPU
program) for the award of a Ph.D. grant.
Conflict of Interest
The authors declare no conflict of interest.
References and Notes
1. Sethna, S.M.; Shah, N.M. The chemistry of coumarins. Chem. Rev. 1945, 36, 1-62.
2. Murray, R.D.; Méndez, J.; Brown, S.A. The Natural Coumarins: Occurrence, Chemistry &
Biochemistry; John Wiley & Sons: New York, NY, USA, 1982.
3. Hoult, J.R.S.; Payá, M. Pharmacological and biochemical actions of simple coumarins: Natural
products with therapeutic potential. Gen. Pharmacol. 1996, 27, 713-722.
4. Coumarins: Biology, Applications and Mode of Action; O´Kennedy, R., Thornes, R.D., Eds.; John
Wiley & Sons: Chichester, UK, 1997.
5. Gambari, R.; Lampronti, I.; Bianchi, N.; Zuccato, C.; Viola, G.; Vedaldi, D.; Dall´Acqua, F.
Structure and biological activity of furocoumarins. Top. Heterocycl. Chem. 2007, 9, 265-276.
6. Conforti, F.; Marrelli, M.; Menichini, F.; Bonesi, M.; Statti, G.; Provenzano, E.; Menichini, F. Natural
and synthetic furanocoumarins as treatment for vitiligo and psoriasis. Curr. Drug Ther. 2009, 4, 38-58.
7. Santana, L.; Uriarte, E.; Roleira, F.; Milhazes, N.; Borges, F. Furocoumarins in medicinal
chemistry. Synthesis, applications, and biological activity. Curr. Med. Chem. 2004, 11, 3239-3261.
8. Traven, V.F. New synthetic routes to furocoumarins and their analogs: A review. Molecules 2004,
9, 50-66.
9. Lee, Y.R.; Byun, M.W.; Kim, B.S. Efficient one-step synthesis of 2-arylfurans by ceric
ammonium nitrate (CAN)-mediated cycloaddition of 1,3-dicarbonyl compounds to alkynes.
Bull. Korean Chem. Soc. 1998, 19, 1080-1083.
10. Kobayashi, K.; Sakashita, K.; Akamatsu, H.; Tanaka, K.; Uchida, M.; Uneda, T.; Kitamura, T.;
Morikawa, O.; Konishi, H. CAN-mediated formation of furopyranones and furoquinolinones.
Heterocycles 1999, 51, 2881-2892.
11. Lee, Y.R.; Suk, J.Y.; Kim, B.S. Rhodium(II)-catalyzed reactions of 3-diazo-2,4-chromenediones.
First one-step synthesis of pterophyllin 2. Tetrahedron Lett. 1999, 40, 6603-6607.
12. Tollari, S.; Palmisano, G.; Cenini, S.; Crovotto, G.; Giovenzana, G.B.; Penoni, A. Synthesis of
furocoumarins via rhodium(II)-catalysed heterocyclisation of 3-diazobenzopyran-2,4(3H)-dione
with terminal alkynes. Synthesis 2001, 735-740.
13. Cheng, G.; Hu, Y. One-pot synthesis of furocoumarins through cascade addition-cyclization-
oxidation. Chem. Commun. 2007, 3285-3287.

Molecules 2011, 16
6479
14. Cheng, G.; Hu, Y. Two efficient cascade reactions to synthesize substituted furocoumarins.
J. Org. Chem. 2008, 73, 4732-4735.
15. Conreaux, D.; Belot, S.; Desbordes, P.; Monteiro, N.; Balme, G. Et3N-Induced demethylation-
annulation of 3-alkynyl-4-methoxy-2-pyridonas and structurally related compounds in the
synthesis of furan-fused heterocycles. J. Org. Chem. 2008, 73, 8619-8622.
16. Raffa, G.; Rusch, M.; Balme, G.; Monteiro, N. A Pd-catalyzed heteroannulation approach to 2,3-
disubstituted furo[3,2-c]coumarins. Org. Lett. 2009, 11, 5254-5257.
17. Chen, L.; Li, Y.; Xu, M.-H. One-pot synthesis of furocoumarins via sequential Pd/Cu-catalyzed
alkynylation and intramolecular hydroalkoxylation. Org. Biomol. Chem. 2010, 8, 3073-3077.
18. Cadierno, V.; Gimeno, J.; Nebra, N. A novel propargylation/cycloisomerization tandem process
catalyzed by a ruthenium(II)/trifluoroacetic acid system: One-pot entry to fully substituted furans
from readily available secondary propargylic alcohols and 1,3-dicarbonyl compounds. Adv. Synth.
Catal. 2007, 349, 382-394.
19. Albers, J.; Cadierno, V.; Crochet, P.; García-Garrido, S.E.; Gimeno, J. Octahedral ruthenium(II)
complexes cis,cis-[RuX2(CNR)(CO)(P^P)] and cis,cis,cis-[RuX2(CO)2(P^P)] (X = Cl, Br; P^P =
1,1’-bis(diphenylphosphino)ferrocene, 1,1’-bis(diisopropylphosphino)ferrocene): Synthesis and
catalytic applications in transfer hydrogenation of acetophenone and cycloisomerization of (Z)-3-
methylpent-2-en-4-yn-1-ol. J. Organomet. Chem. 2007, 692, 5234-5244.
20. Cadierno, V.; Gimeno, J.; Nebra, N. One-pot three-component catalytic synthesis of fully
substituted pyrroles from readily available propargylic alcohols, 1,3-dicarbonyl compounds and
primary amines. Chem. Eur. J. 2007, 13, 9973-9981.
21. Cadierno, V.; Díez, J.; Gimeno, J.; Nebra, N. Ruthenium/TFA catalyzed coupling of activated
secondary propargylic alcohols with cyclic 1,3-diones: Furan vs. pyran ring formation. J. Org.
Chem. 2008, 73, 5852-5858.
22. Cadierno, V.; Crochet, P. Ruthenium-catalyzed furan- and pyrrole-ring formation. Curr. Org.
Synth. 2008, 5, 343-364.
23. Cadierno, V.; Gimeno, J.; Nebra, N. One-pot three-component synthesis of tetrasubstituted N–H
pyrroles from secondary propargylic alcohols, 1,3-dicarbonyl compounds and tert-butyl
carbamate. J. Heterocycl. Chem. 2010, 47, 233-236.
24. García-Garrido, S.E.; Francos, J.; Cadierno, V.; Basset, J.M.; Polshettiwar, V. Chemistry by
nanocatalysis: First example of a solid-supported RAPTA complex for organic reactions in
aqueous medium. ChemSusChem 2011, 4, 104-111.
25. Cadierno, V.; García-Garrido, S.E.; Gimeno, J.; Nebra, N. Atom-economic transformations of
propargylic alcohols catalyzed by the 16-electron allyl-ruthenium(II) complex [Ru(η3-2-
C3H4Me)(CO)(dppf)][SbF6] (dppf = 1,1’-bis(diphenylphosphino)ferrocene). Inorg. Chim. Acta
2010, 363, 1912-1934.
26. Huang, W.; Wang, J.; Shen, Q.; Zhou, X. Yb(OTf)3-catalyzed propargylation and allenylation of
1,3-dicarbonyl derivatives with propargylic alcohols: One-pot synthesis of multisubstituted
furocoumarin. Tetrahedron 2007, 63, 11636-11643.
27. Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-VCH: Weinheim, Germany, 2006.
28. Kappe, C.O.; Dallinger, D.; Murphee, S.S. Practical Microwave Synthesis for Organic Chemists;
Wiley-VCH: Weinheim, Germany, 2009.

Molecules 2011, 16
6480
29. Microwave Heating as a Tool for Sustainable Chemistry; Leadbeater, N.E., Ed.; CRC Press: Boca
Raton, FL, USA, 2011.
30. Sawhney, K.N.; Mathur, K.B.L. Studies on some structural aspects of 4-hydroxycoumarin:
Further extension of Meerwein´s diazo reaction and a substitution reaction involving 2-chloro-2-
methylbut-yne. Indian J. Chem. B: Org. Chem. 1976, 14, 518-521.
31. Chênevert, R.; Pagé, J.; Plante, R.; Beaucage, D. Synthesis of 4,4-dimethyl-5-methylene-4,5-
dihydrofurans. Synthesis 1982, 75-77.
32. Chênevert, R.; Pagé, J.; Voyer, N. Synthesis of (±)-dehydroxyglaupalol and analogs. Synth.
Commun. 1984, 14, 737-742.
33. Reisch, J.; Dharmaratne, H.R.W. A convenient synthesis of the 2-dimethyl-2H-chromene system.
Z. Naturforsch. B 1985, 40, 636-638.
34. Mitra, J.; Mitra, A.K. Palladium(II) assisted cyclization of hydroxyallylcoumarins. Indian J.
Chem. B: Org. Chem. 1994, 33, 276-279.
35. Berger, S.; Haak, E. Ruthenium-catalyzed addition of carboxylic acids or cyclic 1,3-dicarbonyl
compounds to propargylic alcohols. Tetrahedron Lett. 2010, 51, 6630-6634.
36. Cadierno, V.; Díez, J.; García-Garrido, S.E.; Gimeno, J. [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6]: A
mononuclear 16e− ruthenium(II) catalyst for propargylic substitution and isomerization of
HCCCPh2(OH). Chem. Commun. 2004, 2716-2717.
37. Midland, M.M. Preparation of monolithium acetylide in tetrahydrofuran. Reaction with aldehydes
and ketones. J. Org. Chem. 1975, 40, 2250-2252.
38. CrysAlisPro CCD & CrysAlisPro RED; Oxford Diffraction Ltd.: Oxford, UK, 2008.
39. Farrugia, L.J. WinGX suite for small-molecule single-crystal crystallography. J. Appl. Crystallogr.
1999, 32, 837-838.
40. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A. Completion and refinement of
crystal structures with SIR92. J. Appl. Crystallogr. 1993, 26, 343-350.
41. Sheldrick, G.M. SHELXL97: Program for the Refinement of Crystal Structures; University of
Göttingen: Göttingen, Germany, 1997.
42. International Tables for X-Ray Crystallography; Kynoch Press: Birminghan, UK, 1974, Volume
IV (present distributor: Kluwer Academic Publishers: Dordrecht, The Netherlands).
43. Spek, A.L. PLATON: A multipurpose Crystallographic Tool; University of Utrecht: Utrecht, The
Netherlands, 2006.
Sample Availability: Samples of the compounds 4a–d and 5b are available from the authors.
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