Coupled domino processes: Synthesis of 3,5,8-trisubstituted coumarins from propargyl vinyl ethers

Article abstract of DOI:10.1021/jo401202z

The generation of a small and representative library of 3,5,8-trisubstituted coumarins (21 compounds, 7 families, 3 groups) is described. The library was built from the corresponding propargyl vinyl ethers and three different 1,3-dicarbonyl derivatives us

Full text of DOI:10.1021/jo401202z

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Note
Coupled Domino Processes: Synthesis of 3, 5, 8-
Trisubstituted Cou-marins from Propargyl Vinyl Ethers.
David Tejedor, Leandro Cotos, and Fernando Garcia-Tellado
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401202z • Publication Date (Web): 29 Jul 2013
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The Journal of Organic Chemistry
Coupled Domino Processes: Synthesis of 3, 5, 8-Trisubstituted Cou-
marins from Propargyl Vinyl Ethers.
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David Tejedor,* Leandro Cotos and Fernando García-Tellado*
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Instituto de Productos Naturales y Agrobiología, Consejo Superior de Investigaciones Científicas, Astro-
físico Francisco Sánchez 3, 38206. La Laguna, Tenerife, Spain.
fgarcia@ipna.csic.es; dtejedor@ipna.csic.es
KEYWORDS : coumarins; 3,5,8-trisubstituted coumarins; propargyl vinyl ethers; pyridine-catalyzed;
[3.3]sigmatropic rearrangement; Claisen rearrangement; salicylaldehydes; coupled domino; micro-
wave; Knoevenagel; coumarin chemotypes;
ABSTRACT: The generation of a small and representative library of 3, 5, 8 - trisubstituted coumarins
(21 compounds, 7 families, 3 groups) is described. The library was built from the corresponding propar-
gyl vinyl ethers and three different 1,3-dicarbonyl derivatives using a one pot coupled domino strategy.
These coumarins constitute a novel chemotype defined by the presence of a chemical handle in the py-
ranone ring and a varied substitution pattern adorning the aromatic ring, which includes fluorine or oxy-
gen-containing functionalities.
Coumarins (2H-benzo-pyran-2-ones) comprise a large family of natural scaffolds provided with a broad
spectrum of biological and pharmaceutical activities1 and a privileged array of physicochemical proper-
ties such as a high capacity of fluorescence,2 which has been conveniently exploited in analytical chem-
istry, biology and medicine.3 In general, the substitution pattern decorating these scaffolds largely de-
termines their activity profiles1 and modulates their physicochemical properties.4 Thus, novel substitu-
tion patterns could offer novel pharmacological (therapeutic) annotations and novel biological and phys-
icochemical properties.3,5 From a chemical point of view, the access to novel coumarin chemotypes can
be achieved either by chemical modifications of an existing one6 or by de novo synthesis from suitable
precursors. Where the first approach usually requires chemoselective manipulation of functional groups,
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the second one calls for a synthetic methodology capable of directly constructing the coumarin core
with the appropriate substitution pattern already installed. This approach offers new opportunities for
synthetic innovation and very especially for the development of novel domino methodologies for using
in drug discovery and development. With this idea in mind, we report herein our results in the develop-
ment of a fast, operationally simple, one-pot coupled domino manifold for accessing novel 3, 5, 8 - tri-
substituted coumarins 3 from readily available propargyl vinyl ethers 1 (Scheme 1).
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Scheme 1. Synthetic access to 3, 5, 8-trisubstituted coumarins 3.
The substitution pattern involving the positions C3, C5 and C8 (Scheme 1) is scarcely represented in
the series of both natural and synthetic coumarins7 and its biological (therapeutic) annotation has not
been conveniently studied. The main reason for this lack of information is the challenging access to this
family of trisubstituted coumarins by standard synthetic methodologies. In general, coumarins are cur-
rently synthesized from the corresponding phenolic derivatives8 conveniently functionalized (generally
functionalized salicylaldehydes) by condensation with a suitable carbonyl derivative (Scheme 1).1,8 The
main limitation associated with these strategies lies on their lack of generality and efficiency; not all of
the positions of the aromatic and pyranone rings can be accessed from readily obtained salicylalde-
hydes. This issue directly translates the problem of coumarin functionalization to the corresponding par-
ent salicylaldehydes which are usually obtained by the direct formylation of the corresponding function-
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alized phenolic derivatives.9 Recently, our group described a diversity-oriented domino synthesis of 3, 6
- disubstituted salicylaldehyde, derivatives 2 from propargyl vinyl ethers 1 (PVEs) (Scheme 2).10 We
envisioned that these structures could be serve as suitable starting materials for the synthesis of 3, 5, 8 -
trisubstituted coumarins 3 through a domino Knoevenagel condensation/lactonization reaction with an
appropriated carbonyl derivative. Therefore, this strategy would allow us to perform the whole trans-
formation in one pot directly from the PVE with a good overall efficiency (Scheme 2). (Domino I:
[3,3]-sigmatropic rearrangement - diene isomerization - enolization - 6-electro-cyclization; Domino II:
Knoevenagel condensation - lactonization).
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Scheme 2. Domino coupled synthesis of 3, 6 - disubstituted coumarins 3 from propargyl vinyl ethers 1.
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From our previous studies on the salicylaldehyde formation reaction (Scheme 2),10 we knew that
the in situ produced methanol (one equivalent of methanol is generated in the formation of salicylalde-
hyde 2) had to be removed from the reaction media to avoid the competitive formation of alkene 7,
which is generated by methanol addition on 5 and redox rearrangement of the resulting hemiacetal.11
This redox process could be avoided by using activated powdered molecular sieves 4Ǻ (MS 4Ǻ) as an
additive. A fortuitous discovery showed us that also pyridine, a nucleophilic base, inhibited the for-
mation of the alkene.7 It is not easy to imagine pyridine as a methanol scavenger; instead, we believe
that both additives assist in the enolization of intermediate 5 to give triene 6 which is not a suitable elec-
trophile for methanol. If intermediate 5 is quickly enolized, then its concentration will be maintained
low and the formation of alkene 7 will be inhibited or severely diminished. There are precedents for the
enolization of nitroalkanes aided by MS 4Ǻ.12 We found that the microwave irradiation of a solution of
PVE 1 in xylene (1 mmol/1ml) [200 ºC, 300 W, 1h, closed vessel] in the presence of two equivalents of
pyridine afforded the corresponding salicylaldehydes 2 with a comparable efficiency to the same pro-
cess in the presence of MS 4Ǻ (Table 1). Whereas pyridine offers a similar or slightly lower efficiency
than MS 4Ǻ for substrates involving an aromatic or an ester group (diene activating groups) (entries 1-
4), it is the best option in the case of alkyl substitution at the terminal and propargylic positions (entry
5). It is noteworthy that in these cases pyridine offers a clear advantage over MS 4Ǻ either in terms of
instrumental simplicity (the reaction is performed under homogeneous conditions) and yields (54% ver-
sus 44%). Oxygen-containing and fluoride-containing derivatives can be accessed with pyridine as addi-
tive in fairly good yields (entries 6 and 7).
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Once the pyridine-assisted reaction could be standardized, we went one step further and we studied
the transformation of these substituted salicylaldehydes 2a-g into coumarins 3 featuring different
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Table 1. Effect of additive in the microwave-assisted domino formation of salicylaldehydes 2 from
PVEs 1.
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Entry
Py (%)a
75
MS 4Ǻ (%)a,b
R1
Ph
R2
Et
2
a
b
c
d
e
f
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89
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--
Ph
Ph
tBu
Pr
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Ph
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CO2Me
Bu
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Et
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Ph
F
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Ph
OBn
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g
aYield of isolated compounds. bSee Rf. 10.
substituents at the C3 position. For this transformation we explored a domino Knoevenagel condensa-
tion/lactonization protocol,1,8 involving 1,3-dicarbonyl derivatives armed with at least one ester group
and salicylaldehydes 2a-g. This domino reaction can be base-catalyzed (through the formation of the
enolate anion of the active methylene derivative) or iminium-catalyzed (through the formation of the
corresponding iminium ion derivative of the aromatic aldehyde).13 As a first approximation, we chose
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the base catalyzed version in hopes that we would be able to connect this domino reaction with the pyri-
dine-assisted domino formation of salicylaldehydes 2 (Scheme 2). After several experimental attempts
using different malonate derivatives, different bases and different reaction conditions (temperature, sol-
vent), we were unable to run the whole process directly from the PVE: the set of experimental condi-
tions that sparked a domino process were unfavorable for the other and vice versa. Thus, we turned our
attention to a one pot strategy. We explored this possibility using the iminium catalyzed conditions for
the Knoevenagel reaction.13 After several experimental attempts using different catalysts and conditions,
we arrived to piperidinium acetate (PPA) (5 mol%) as the best catalyst and refluxing ethanol as the
more convenient reaction conditions. The one pot process could be performed by first running the mi-
crowave-assisted formation of the salicylaldehyde intermediate 2 and then, once the solvent and base
were distilled off, running the second domino reaction on the crude reaction residue.
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For this study, we chose three different carbonyl derivatives, i.e. ethyl acetoacetate, Meldrum’s acid
and ethyl cyanoacetate, to generate the corresponding coumarins 3 armed with an ester, acid or nitrile
group at the C3 position. Each Knoevenagel reaction required a fine tuning of the experimental condi-
tions to be performed with synthetic efficiency (Scheme 3; conditions A, B and C). Ethyl acetoacetate
reacted with salicylaldehydes 2a-g (conditions A) to afford the corresponding 3-acyl-coumarins 3ab-gb
in good overall yields (70% average yield per domino process). The more reactive Meldrum’s acid re-
quired more catalyst (20 mol%)(conditions B) to be transformed into the corresponding coumarins 3ac-
gc with moderate to good efficiency (overall yields span from a modest 30% to a fairly good 57%). The
less reactive and less acidic ethyl cyanoacetate required catalysis and microwave irradiation [100 ºC,
300 W, 1h, closed vessel] (conditions C) to accomplish this transformation. Under these conditions, it
afforded the corresponding coumarins 3aa-ga featuring a chemically versatile nitrile group at C3.14 It
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Conditions: (A): R3 = Ac, EtOH (3 ml), PPA (5 mol%), reflux, 16h. (B): Meldrum's acid, EtOH (3 ml), PPA (20
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mol%), reflux, 2h. (C): R3 = CN, [100 ºC, 300 W], xylene (1 ml), PPA (5 mol%); 1h, closed vessel.
Scheme 3. Synthesis of 3, 5, 8 - trisubstituted coumarins 3 from PVEs 1 by one pot coupled domino
processes.
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should be noted that the substituents at the C3 and C6 positions of salicylaldehydes 2a-g exercise an im-
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portant steric impediment to these reactions, which translates to the overall yield of the process, slightly
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lower than those reported for salicylaldehyde derivatives with these positions free of substitution.1,8 Last
but not least, coumarins armed with a fluorine atom (3fa-fc) or an oxygen-containing functionality (3ga-
gc) at the C8 position can be generated in good overall yields under conditions A and B and with lower
efficiency under conditions C.
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In summary, we have generated a representative library of 21 different 3, 5, 8- trisubstituted couma-
rins grouped in 7 families of 3 members each. This representative library was built using a one pot cou-
pled domino process manifold. The one pot process takes advantage of the fortuitous discovery of the
pyridine-aided domino generation of salicylaldehydes 2 under microwave irradiation. This instrumental-
ly simple coupled domino manifold allows for the fast access to a novel coumarin chemotype defined by
its substitution pattern at the aromatic ring (C5, C8 - functionalization). These chemotypes feature a
chemical handle in the pyranone ring (C3-position) for further elaboration and a diverse substitution
pattern at the aromatic ring, including aliphatic, aromatic, carboxylic esters, fluorine or oxygen-
containing functionalities.
EXPERIMENTAL SECTION
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General information. H NMR and C NMR spectra of CDCl3 solutions were recorded either at 400
and 100 MHz or at 500 and 125 MHz, respectively. Microwave reactions were conducted in sealed glass
vessels (capacity 10 mL) using a CEM Discover microwave reactor equipped with a surface sensor for
temperature measuring of the reaction mixture. FT-IR spectra were measured in chloroform solutions
using a FT-IR spectrophotometer. Mass spectra (low resolution) (EI/CI) and HRMS (EI/TOF) were ob-
tained with a gas chromatograph/mass spectrometer. Analytical thin-layer chromatography plates used
UV-active silica on aluminum. Flash column chromatography was carried out with silica gel of particle
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size less than 0.020 mm, using appropriate mixtures of ethyl acetate and hexanes as eluents. All reac-
tions were performed in oven-dried glassware. All materials were obtained from commercial suppliers
and used as received unless otherwise noted. Propargyl vinyl ethers (PVEs) were synthesized according
to literature procedures (1a-c, 1e-g),15 and (1d).16 When not commercially available, the propargyl alco-
hols were prepared by addition of the lithium acetylides onto the appropriate aldehydes following the
literature procedure.17 All other materials were obtained from commercial suppliers and used as re-
ceived. Products 1a-f, have been previously reported and all data are in accordance with those of the
literature. 10
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Synthesis of (E)-Methyl 3-(1-(benzyloxy)-4-phenylbut-3-yn-2-yloxy)acrylate (1g). Triethylamine
(0.30 mmol) was added to a solution of methyl propiolate (3.0 mmol) and 1-(benzyloxy)-4-phenylbut-3-
yn-2-ol (3.0 mmol) in dry CH2Cl2 (10 ml). The reaction mixture was stirred for 2 h. After removing the
solvent at reduced pressure the products were purified by flash column chromatography (silica gel, n-
1
hexane/EtOAc 90/10) to yield 1g (959 mg; 89%) (gummy oil): H NMR (CDCl3, 400 MHz):  3.70
(s, 3H), 3.82-3.84 (m, 2H), 4.61 (d, 3J(H,H) = 12.1 Hz, 1H), 4.67 (d, 3J(H,H) = 12.1 Hz, 1H), 4.97 (t, 3J(H,H)
3
3
= 5.8 Hz, 1H), 5.46 (d, J(H,H) = 12.6 Hz, 1H), 7.28-7.36 (m, 8H), 7.41-7.44 (m, 2H), 7.70 (d, J(H,H)
=
13
12.6 Hz, 1H) ppm. C NMR (CDCl3, 100 MHz): = 51.1, 71.9, 73.6, 82.5, 88.9, 98.9, 121.5, 127.8,
127.9, 128.4, 128.5, 129.1, 131.9, 137.5, 160.6, 167.9 ppm. FTIR (CHCl3): 3065.5, 3028.1, 3014.9,
2952.4, 2909.2, 2867.9, 2229.01, 1953.3, 1884.5, 1705.3, 1643.7, 1626.3, 1492.3, 1439.7 cm-1. HRMS
(EI-TOF) m/z: [M+ + Na] Calcd for C21H20O4Na 359.1259. Found 359.1259.
Representative procedure for the microwave-assisted rearrangement of propargyl vinyl ether 1 in
the presence of pyridine. Synthesis of salicylaldehydes 2. Propargyl vinyl ether 1g (1.00 mmol), o-
xylene (1 mL) and pyridine (2.00 mmol) were placed in a microwave-special closed vial and the solu-
tion was irradiated for 1 hour in a single-mode microwave oven (300 Watt, 200 ºC). After removing the
solvent at reduced pressure the products were purified by flash column chromatography (silica gel, ap-
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1
propriate mixtures of ethyl acetate / hexane) to yield 2g (212.8 mg; 70%). Amorphous solid. H NMR
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(CDCl3, 400 MHz):  5.23 (s, 2H), 6.76 (d, 3J(H,H) = 8.3 Hz, 1H), 7.13 (d, 3J(H,H) = 8.33 Hz, 1H), 7.31-
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7.37 (m, 3H), 7.41-7.48 (m, 7H), 9.83 (s, 1H), 12.18 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): =
6
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71.6, 18.3, 120.7, 120.8, 127.4, 127.9, 128.1, 128.4, 128.7, 130.2, 136.7, 137.5, 139.5, 146.7, 153.7,
197.6 ppm; FTIR (CHCl3): 3027.9, 2887.2, 1644.1, 1570.6, 1449.3, 1393.5 cm-1; LRMS (70 eV)
m/z (%): 304 (7.2) [M+], 139 (8.2), 128 (10), 91 (100). HRMS (EI-TOF) m/z: [M]+ Calcd for C20H16O3
304.1107; Found 304.1099.
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Representative procedure for the synthesis of coumarins bearing an acetate at the 3-position
(Conditions A). Propargyl vinyl ether 1a (1.00 mmol), o-xylene (1 mL) and pyridine (2.00 mmol) were
placed in a microwave-special closed vial and the solution was irradiated for 1 hour in a single-mode
microwave oven (300 Watt, 200 ºC). After the time described, the sample was cooled to room tempera-
ture and the crude of the reaction was redissolved in 3 mL of ethanol. Ethyl acetoacetate (1.1 mmol) and
piperidine (0.05 mmol) were added and the solution was refluxed during 20 hours. After that time, the
solvent was removed at reduced pressure. The products were purified by flash column chromatography
(silica gel, appropriate mixtures of dichloromethane / hexane) to yield 3aa (204.4 mg; 70%).
1
3-Acetyl-8-ethyl-5-phenyl-2H-chromen-2-one (3aa). Amorphous solid. H NMR (CDCl3, 400 MHz):
3
3
3
 1.33 (t, J(H,H) = 7.6 Hz, 3H), 2.68 (s, 3H), 2.94 (q, J(H,H) = 7.58 Hz, 2H), 7.23 (d, J(H,H) = 7.6 Hz,
3
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1H), 7.31-7.33 (m, 2H), 7.44-7.49 (m, 3H), 7.53 (d, J(H,H) = 7.6 Hz, 1H), 8.53 (s, 1H) ppm. C NMR
(CDCl3, 100 MHz): = 14.0, 22.5, 30.5, 116.2, 123.9, 125.7, 128.4, 129.8, 131.1, 133.6, 137.6, 141.8,
146.4, 153.8, 159.1, 195.7 ppm. FTIR (CHCl3): 3025.9, 2974.9, 2877.3, 1954.9, 1905.8, 1729.9,
1688.3, 1581.5 cm-1. Anal. Calcd for C19H16O3: C, 78.06; H, 5.52. Found: C, 77.8; H, 5.69. LRMS (70
eV) m/z (%): 292 (90) [M+], 277 (100), 249 (33) 235 (13), 207 (16), 193 (13), 178 (29), 165 (22), 152
(10), 84 (34).
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1
3-Acetyl-5,8-diphenyl-2H-chromen-2-one (3ba). (227.8 mg; 67%). Amorphous solid. H NMR
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(CDCl3, 400 MHz): sm, 3H), 7.44- 7.45 (m, 1H), 7.49-7.55(m, 5H), 7.64-
3
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7.67 (m, 2H), 7.72 (t, J(H,H) = 7.83, 1H), 8.59 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 30.4,
116.8, 124.1, 125.9, 128.3, 128.6 (2C), 128.7, 128.9, 129.2, 129.5 (2C), 129.8 (2C), 134.8, 135.2, 137.4,
143.3, 146.2, 152.7, 158.6, 195.5 ppm. FTIR (CHCl3): 3025.3, 1736.2, 1690.0, 1584.7, 1574.8 cm-
1. LRMS (70 eV) m/z (%): 340 (100) [M+], 325 (64), 297 (21), 239 (38), 230 (18), 129 (8.5), 115 (11),
83 (32). HRMS (EI-TOF) m/z: [M]+ Calcd for C23H16 O3 340.1099; Found 340.1109.
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3-Acetyl-8-tert-butyl-5-phenyl-2H-chromen-2-one (3ca). (121.6 mg; 38%). Amorphous solid. H
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NMR (CDCl3, 400 MHz): ss, 3H), 7.23 (d, J(H,H) = 8.1 Hz, 1H), 7.31-7.34 (m,
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2H), 7.45-7.51(m, 3H), 7.66 (d, J(H,H) = 8.1 Hz, 1H), 8.55 (s, 1H) ppm. C NMR (CDCl3, 100 MHz):
= 29.8, 30.5, 35.0, 116.9, 123.2, 125.5, 128.4, 128.8, 129.8, 131.5, 136.9, 137.5, 142.1, 146.7, 154.6,
158.6, 195.5 ppm. FTIR (CHCl3): 3694.7, 3026.5, 3013.6, 2963.9, 2928.8, 2874.8, 2857.0, 1726.4,
1688.3, 1602.3, 1574.3 cm-1. LRMS (70 eV) m/z (%): 320 (45) [M+], 305 (72), 221 (100), 189 (8.4),
165 (12). HRMS (EI-TOF) m/z: [M]+ Calcd for C21H20 O3 320.1412; Found 320.1405.
Methyl 3-acetyl-2-oxo-8-propyl-2H-chromene-5-carboxylate (3da). (115.2 mg; 40%). Amorphous
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solid. 1H NMR (CDCl3, 400 MHz):  0.99 (t, J(H,H) = 7.3 Hz, 3H), 1.68-1.77 (m, 2H) 2.72 (s, 3H),
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2.88 (q, 3J(H,H) = 7.6 Hz, 2H), 3.97 (s, 3H), 7.51 (d, J(H,H) = 7.8 Hz, 1H), 7.89 (d, 3J(H,H) = 7.8 Hz, 1H),
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9.54 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 13.8, 22.6, 30.3, 31.7, 52.6, 117.5, 125.5, 127.3,
127.4, 133.3, 135.6, 145.5, 153.9, 158.1, 165.8, 195.4 ppm. FTIR (CHCl3): 3087.2, 3027.5, 2963.8,
2874.9, 1728.1, 1693.6, 1613.9, 1585.6, 1566.4, 1480.2, 1436.0, 1415.8 cm-1. LRMS (70 eV) m/z (%):
288 (43) [M+], 273 (100), 259 (11), 217 (5.4), 189 (4.5), 115 (6.6), 102 (4.3), 77 (3.1). HRMS (EI-TOF)
m/z: [M]+ Calcd for C16H16 O5 288.0998; Found 288.1000.
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3-Acetyl-5-butyl-8-ethyl-2H-chromen-2-one (3ea). (114.2 mg; 42%). Amorphous solid. H NMR
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(CDCl3, 400 MHz):  0.94 (t, 3J(H,H) = 7.3 Hz, 3H), 1.27 (t, 3J(H,H) = 7.6 Hz, 3H), 1.34-1.44 (m, 2H),
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1.60-1.64 (m, 2H), 2.73 (s, 3H), 2.82-2.90 (m, 4H), 7.07 (d, J(H,H) = 7.6 Hz, 1H), 7.40 (d, J(H,H) = 7.8
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Hz, 1H), 8.43 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 13.8, 13.9, 22.3, 22.4, 30.5, 30.6, 34,
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116.5, 123.2, 125.0, 129.7, 133.9, 141.4, 144.7, 154.0, 159.2, 195.8 ppm. FTIR (CHCl3): 3027.6,
2962.2, 2935.1, 2875.1, 1725.7, 1686.7, 1586.2, 1566.8, 1481.7 cm-1. LRMS (70 eV) m/z (%): 272 (93)
[M+], 257 (100), 229 (72), 215 (17), 201 (20), 187 (12), 173 (8.1), 128 (14), 115 (25), 91 (12). HRMS
(EI-TOF) m/z: [M]+ Calcd for C17H20 O3 272.1411; Found 272.1412.
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3-Acetyl-8-fluoro-5-phenyl-2H-chromen-2-one (3fa). (115.6 mg; 41%). Amorphous solid. H NMR
(CDCl3, 400 MHz): s, 3H), 7.25 (dd, 3J(H,H) = 8.3 Hz, 4.6, 1H), 7.31-7.33 (m, 2H), 7.42-7.50
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(m, 4H), 8.47 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 30.4, 118.0, 120.0 (JCF = 17.0), 125.0,
125.6 (JCF = 5.7), 128.7, 128.9, 129.7, 136.7, 139.5 (JCF = 4.2), 143.7 (JCF = 11.3), 145.6, 148.4 (JCF =
253.6), 157.6, 195.1 ppm. FTIR (CHCl3): 3026.9, 1887.3, 1693.2, 1604.6, 1571.3 cm-1. LRMS (70
eV) m/z (%): 282 (74) [M+], 267 (100), 238 (45), 212 (12), 183 (87), 163 (13), 157 (11), 84 (66). HRMS
(EI-TOF) m/z: [M]+ Calcd for C17H11FO3 282.0692; Found 282.0688.
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3-Acetyl-8-(benzyloxy)-5-phenyl-2H-chromen-2-one (3ga). (236.8 mg; 64%). Amorphous solid. H
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NMR (CDCl3, 400 MHz):  2.69 (s, 3H), 5.30 (s, 2H), 7.17-7.51 (m, 12H), 8.51 (s, 1H) ppm. C
NMR (CDCl3, 100 MHz): = 30.4, 71.5, 117.2, 118.1, 124.4, 125.5, 127.3, 128.1, 128.2, 128.7, 128.8,
129.8, 135.8, 136.1, 137.3, 145.2, 145.9, 146.2, 158.5, 195.6 ppm. FTIR (CHCl3):  3064.9, 3028.2,
3015.6, 2931.0, 1733.4, 1690.1, 1612.6, 1592.2, 1561.7 cm-1. LRMS (70 eV) m/z (%): 370 (3.6) [M+],
237 (1.9), 176 (4.9), 152 (10), 129 (22), 115 (12), 91 (100), 77 (10), 65 (16). HRMS (EI-TOF) m/z:
[M]+ Calcd for C24H18O4 370.1205; Found 370.1193.
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Representative procedure for the synthesis of coumarins bearing a carboxylic acid at the 3-
position. (Conditions B). Propargyl vinyl ether 1a (1.00 mmol), o-xylene (1 mL) and pyridine (2.00
mmol) were placed in a microwave-special closed vial and the solution was irradiated for 1 hour in a
single-mode microwave oven (300 Watt, 200 ºC). After removing the solvent at reduced pressure the
products were redissolved in ethanol. Meldrum acid (1.1 mmol) and piperidinium acetate (0.2 mmol)
were added. The solution was refluxed with stirring during 2 hours. The solvent was removed at reduced
pressure. The products were purified by flash column chromatography (silica gel, appropriate mixtures
of dichloromethane/MeOH) to yield 3ab (138.2 mg; 47%).
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8-ethyl-2-oxo-5-phenyl-2H-chromene-3-carboxylic acid (3ab). Amorphous solid. H NMR (CD3OD, 400
MHz 1.29 (t, 3J(H,H) = 7.6 Hz, 3H), 2.9 (q, 3J(H,H) = 7.6 Hz, 2H), 7.28 (d, 3J(H,H) = 7.3 Hz, 1H), 7.36-
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7.38 (m, 2H), 7.44-7.48 (m, 3H), 7.6 (d, J(H,H) = 7.6 Hz, 1H), 8.6 (s, 1H) ppm. 13C NMR (CDCl3, 100
MHz): 19.4, 22.5, 116.7, 126.8, 128.7, 129.0, 129.8, 131.6, 134.7, 136.9, 142.1, 150.2, 153.0, 163.2,
163.6 ppm. FTIR (CHCl3):  3070.1, 2995.6, 2949.7, 2914.3, 1757.6, 1680.9, 1590.0, 1473.9 cm-1.
Anal. Calcd for C18H14O4: C, 73.46; H, 4.79. Found: C, 73.56; H, 4.60. LRMS (70 eV) m/z (%):
294(100) [M+], 279 (16), 250(71), 235 (47), 207 (37), 193 (26), 178 (43), 165 (30), 152 (20), 115 (15),
89 (13), 84 (12), 77 (11).
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2-Oxo-5,8-diphenyl-2H-chromene-3-carboxylic acid (3bb). (143.6 mg; 42%). Amorphous solid. H
NMR (CDCl3, 400 MHz):  7.40 (d, 3J(H,H) = 7.1 Hz, 2H), 7.45-7.55 (m, 7H), 7.62 (d, 3J(H,H) = 7.3 Hz,
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2H), 7.84 (d, J(H,H) = 7.8 Hz, 1H), 9.03 (s, 1H), 12.14 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): =
114.3, 117.2, 127.1, 128.6, 128.8 (2C), 129.1, 129.2 (2C), 129.4 (2C), 129.7 (2C), 129.8, 134.5, 136.2,
136.7, 143.7, 150.5, 151.9, 162.5, 163.6 ppm. FTIR (CHCl3):  3692.4, 3063.9, 3027.8, 2962.7,
1758.9, 1682.1, 1590.8, 1471.5, 1453.8, 1397.6 cm-1). LRMS (70 eV) m/z (%): 342 (100) [M+], 298
(30), 270 (19), 256 (14), 239 (34), 133 (12),129 (28), 128 (17). HRMS (EI-TOF) m/z: [M]+ Calcd for
C22H14O4 342.0892; Found 342.0886.
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8-tert-Butyl-2-oxo-5-phenyl-2H-chromene-3-carboxylic acid (3cb). (138.5 mg; 43%). Amorphous
solid. 1H NMR (CD3OD, 400 MHz): 1.49 (s, 9H), 7.28 (d, 3J(H,H) = 7.6 Hz, 1H), 7.35-7.37 (m, 2H),
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7.45-7.48 (m, 3H), 7.74 (d, J(H,H) = 7.6 Hz, 1H), 8.63 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): =
29.8 (3C), 35.1, 117.3, 126.6, 128.7, 128.9 (2C), 129.7 (2C), 132.8, 136.8, 137.4, 142.5, 150.7, 153.8,
163.34, 163.38 ppm. LRMS (70 eV) m/z (%): 322 (51) [M+], 307 (67), 221 (100), 178 (12)165 (14), 84
(29). HRMS (EI-TOF) m/z: [M]+ Calcd for C20H18O4 322.1205; Found 322.1201.
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5-(Methoxycarbonyl)-2-oxo-8-propyl-2H-chromene-3-carboxylic acid (3db). (107.3 mg; 37%).
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Amorphous solid. H NMR (CDCl3, 400 MHz): 1.00 (t, J(H,H) = 7.3 Hz, 3H), 1.69-1.79 (m, 2H),
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2.92 (q, J(H,H) = 8.1 Hz, 2H), 4.00 (s, 3H), 7.64 (d, J(H,H) = 8.09 Hz, 1H), 8.02 (d, J(H,H) = 7.83 Hz,
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1H), 10.03 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): =13.8, 22.6, 31.6, 52.9, 115.7, 117.7, 127.6,
128.5, 134.8, 136.2, 150.1, 153.2, 162.2, 163.1, 165.3 ppm. FTIR (CHCl3): 3030.4, 2996.9, 2957.9,
2935.3, 1757.7, 1723.0, 1686.0, 1620.9, 1588.5, 1484.4, 1437.1, 1398.6 cm-1. Anal. Calcd for
C15H14O6: C, 62.07; H, 4.86. Found: C, 62.31; H, 4.83. LRMS (70 eV) m/z (%): 290 (29) [M+], 261
(36), 246 (100), 232 (27), 217 (18), 189 (11), 161 (10), 115
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5-Butyl-8-ethyl-2-oxo-2H-chromene-3-carboxylic acid (3eb). (74 mg; 27%). Amorphous solid. H
NMR (CDCl3, 400 MHz):  0.95 (t, 3J(H,H) = 7.3 Hz, 3H), 1.29 (t, 3J(H,H) = 7.6 Hz, 3H), 1.34-1.45 (m,
2H), 1.58-1.66 (m, 2H), 2.86-2.95 (m, 4H), 7.20 (t, 3J(H,H) = 7.6 Hz, 1H), 7.52 (t, 3J(H,H) = 7.6 Hz, 1H),
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9.14 (s, 1H), 12.42 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 13.8, 13.9, 22.3, 22.4, 31.6, 34.1,
113.4, 117.0, 126.3, 130.3, 135.4, 142.0, 148.7, 135.3, 163.0, 164.1ppm. FTIR (CHCl3): 3029.2,
2962.1, 2934.8, 2875.7, 1753.7, 1681.1, 1593.7, 1402.8 cm-1. LRMS (70 eV) m/z (%): 274 (100) [M+],
259 (21), 230 (72), 203 (18), 187 (13), 128 (21), 115 (35), 91 (15), 84 (89), 77 (12). HRMS (EI-TOF)
m/z: [M]+ Calcd for C16H18O4 274.1202; Found 274.1205.
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8-Fluoro-2-oxo-5-phenyl-2H-chromene-3-carboxylic acid (3fb). (133.5 mg; 47%). Amorphous solid.
1H NMR (CDCl3, 400 MHz): 7.32-7.33 (m, 2H), 7.38 (dd, 3J(H,H) = 8.3 Hz, 4.0, 1H), 7.52-7.60 (m,
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4H), 8.93 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 115.4, 118.2, 121.3 (JCF = 16.2 Hz), 126.8
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(JCF = 5.7 Hz), 129.1, 129.2, 129.7, 136.0, 139.9 (JCF = 4.2 Hz), 142.9 (JCF = 12.0 Hz), 148.5 (JCF = 255
Hz), 150, 161.9, 162.5. FTIR (CHCl3): 3619.9, 3464.4, 3015.7, 2976.8, 2928.5, 1759.9, 1699.3,
1687.0, 1608.9, 1582.8 cm-1. LRMS (70 eV) m/z (%): 284 (37) [M+], 240 (44), 212 (33), 198 (21), 183
(100), 181 (23), 163 (17), 157 (12), 97 (15), 83 (27), 69 (37), 55 (62). HRMS (EI-TOF) m/z: [M]+ Calcd
for C16H9FO4 284.0485; Found 284.048.
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8-(Benzyloxy)-2-oxo-5-phenyl-2H-chromene-3-carboxylic acid (3gb). (212 mg; 57%). Amorphous
solid. 1H NMR (CDCl3, 400 MHz):  5.32 (s, 2H), 7.28-7.51 (m, 12H), 8.94 (s, 1H), 12.1 (s, 1H) ppm.
13C NMR (CDCl3, 100 MHz): = 71.7, 114.6, 117.6, 118.9, 126.8, 127.4, 128.5, 128.6, 128.9, 129.1,
130.7, 135.6, 136.0, 136.7, 144.6, 145.5, 150.5, 162.5, 163.6 ppm. FTIR (CHCl3): 3694.2, 3601.2,
3029.8, 3012.2, 1756.8, 1682.5, 1598.4, 1564.3 cm-1. LRMS (70 eV) m/z (%): 372 (9.3) [M+], 333 (4.1),
282 (6.9), 181 (5.7), 152 (21), 91 (100). HRMS (EI-TOF) m/z: [M]+ Calcd for C23H16O5 372.0998;
Found 372.0992.
Representative procedure for the synthesis of coumarins bearing a cyano group at the 3-position.
(Conditions C). Propargyl vinyl ether 1a (1.00 mmol), o-xylene (1 mL) and pyridine (2.00 mmol) were
placed in a microwave-special closed vial and the solution was irradiated for 1 hour in a single-mode
microwave oven (300 Watt, 200 ºC). After the time described the sample was cooled to room tempera-
ture. Ethyl cyanoacetate (1.1 mmol) and piperidine (0.05 mmol) were added and the solution was heated
to 100ºC (300 Watt), during 1 hour. The solvent was then removed at reduced pressure. The products
were purified by flash column chromatography (silica gel, appropriate mixtures of dichloro-
methane/hexane) to yield 3ac (149.9 mg; 57%).
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8-Ethyl-2-oxo-5-phenyl-2H-chromene-3-carbonitrile (3ac). Amorphous solid. H NMR (CDCl3, 400
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MHz):  1.33 (d, 3J(H,H) = 7.6 Hz, 3H), 2.92 (q, 3J(H,H) = 7.6 Hz, 2H), 7.29-7.32 (m, 3H), 7.49-7.55 (m,
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3H), 7.60 (d, J(H,H) = 7.8 Hz, 1H), 8.28 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 13.9, 22.4,
102.4, 113.9, 115.4, 126.3, 128.8, 129.0, 129.7, 131.9, 134.8, 136.8, 140.9, 151.0, 153.1, 156.4 ppm.
FTIR (CHCl3):3064.1, 3026.8, 2973.9, 2934.1, 2876.7, 2236.1, 1906.8, 1743.0, 1588.6, 1473.5,
1215.9 cm-1. Anal. Calcd for C18H13NO2 : C, 78.53; H, 4.76; N, 5.09. Found: C, 78.58; H, 4.76; N, 5.16.
LRMS (70 eV) m/z (%): 275 (100) [M+], 260 (90), 193 (18), 165 (17).
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2-Oxo-5,8-diphenyl-2H-chromene-3-carbonitrile (3bc). (161.5 mg; 50%). Amorphous solid. H NMR
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(CDCl3, 400 MHz):  7.36-7.61 (m, 11H), 7.7 (d, J(H,H) = 7.8 Hz, 1H), 8.34 (s, 1H) ppm. C NMR
(CDCl3, 100 MHz): = 102.7, 113.8, 115.9, 126.5, 128.5, 128.7 (2C), 129.0, 129.1 (2C), 129.4 (2C),
129.7 (2C), 129.9, 134.5, 136.1, 136.6, 142.7, 150.9, 151.9, 155.8 ppm. FTIR (CHCl3):3692.0,
3026.3, 2928.2, 2855.6, 2239.6, 1745.6, 1589.9, 1470.4 cm-1. LRMS (70 eV) m/z (%): 323 (100) [M+],
294 (12), 266 (13), 239 (11), 190 (6.80), 164 (3.30), 128 (8.10), 119 (4.60), 63 (3.90). HRMS (EI-TOF)
m/z: [M]+ Calcd for C22H13N O2 323.0946; Found 323.0937.
8-tert-Butyl-2-oxo-5-phenyl-2H-chromene-3-carbonitrile (3cc). (160.6 mg; 53%). Amorphous solid.
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1H NMR (CDCl3, 400 MHz): 1.53 (s, 9H), 7.28 (d, J(H,H) = 8.1 Hz, 1H), 7.30-7.32 (m, 2H), 7.51-
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7.53 (m, 3H), 7.72 (d, J(H,H) = 8.1 Hz, 1H), 8.28 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 29.8,
35.1, 101.8, 113.9, 116.0, 126.0, 128.8, 129.0, 129.7, 132.7, 136.8, 137.7, 141.3, 151.3, 153.9, 155.8
ppm. FTIR (CHCl3):3692.6, 3063.7, 3025.1, 2963.8, 2876.3, 2237.4, 1742.5, 1618.5, 1582.9 cm-1.
LRMS (70 eV) m/z (%): 303 (26) [M+], 288 (94), 259 (16), 229 (38), 221 (42), 197 (66), 187 (17), 175
(18), 170 (11), 142 (20), 131 (31), 103 (11), 88 (11), 84 (100), 77 (11), 57 (51). HRMS (EI-TOF) m/z:
[M]+ Calcd for C20H17N O2 303.1259; Found 303.1257.
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Methyl 3-cyano-2-oxo-8-propyl-2H-chromene-5-carboxylate (3dc). (89.4 mg; 33%). Amorphous
solid. 1H NMR (CDCl3, 400 MHz): 0.98 (t, 3J(H,H) = 7.3 Hz, 3H) 1.66-01.75 (m, 2H), 2.86 (t, 3J(H,H)
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= 7.8 Hz, 2H) 3.98 (s, 3H), 7.58 (d, J(H,H) = 7.8 Hz, 1H), 7.98 (t, J(H,H) = 7.8 Hz, 1H), 9.59 (s, 1H)
ppm. 13C NMR (CDCl3, 100 MHz): = 13.8, 22.6, 31.6, 52.9, 104.4, 113.6, 116.6, 125.9, 128.1, 134.7,
136.6, 150.5, 153.4, 155.5, 165.4 ppm. FTIR (CHCl3):3092.7, 3028.0, 3001.9, 2961.4, 2934.6,
2875.3, 2237.3, 1742.9, 1720.9, 1618.7, 1586.8, 1482.3, 1436.3 cm-1. LRMS (70 eV) m/z (%): 271 (71)
[M+], 242 (100), 212 (9.8), 155 (6.5), 127 (7.10), 84 (27), 55 (7.2). HRMS (EI-TOF) m/z: [M]+ Calcd
for C15H13N O4 271.0845; Found 271.0837.
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5-Butyl-8-ethyl-2-oxo-2H-chromene-3-carbonitrile (3ec). (56.1 mg; 22%). Amorphous solid. H
NMR (CDCl3, 400 MHz):  0.95 (t, 3J(H,H) = 7.1 Hz, 3H), 1.25 (t, 3J(H,H) = 7.6 Hz, 3H), 1.36-1.45 (m,
2H), 1.55-1.63 (m, 2H), 2.81-2.85 (m, 4H), 7.13 (d, 3J(H,H) = 7.6 Hz, 1H), 7.46 (d, 3J(H,H) = 7.8 Hz, 1H)
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8.45 (s, 1H) ppm. C NMR (CDCl3, 100 MHz): = 13.8, 13.9, 22.2, 22.5, 31.7, 34.1, 101.9, 114.1,
115.6, 125.8, 130.5, 135.2, 140.5, 149.2, 153.3, 156.5 ppm. FTIR (CHCl3):3026.2, 2962.9, 2935.4,
2875.6, 2234.7, 1910.8, 1880.2, 1739.7, 1591.8, 1483.8, 1463.1, 1438.0 cm-1. LRMS (70 eV) m/z (%):
255 (65) [M+], 240 (30), 212 (100), 184 (28), 140 (13), 115 (15), 83 (22). HRMS (EI-TOF) m/z: [M]+
Calcd for C16H17N O2 255.1259; Found 255.1252.
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8-Fluoro-2-oxo-5-phenyl-2H-chromene-3-carbonitrile (3fc). (98.1 mg; 37%). Amorphous solid. H
NMR (CDCl3, 400 MHz):  7.30-7.33 (m, 3H), 7.50-7.55 (m, 4H), 8.25 (d, 3J(H,H) = 1.3 Hz, 1H) ppm.
13C NMR (CDCl3, 100 MHz): = 103.8, 113.3, 116.9, 121.6 (JCF = 17.7 Hz), 126.3 (JCF = 6.4), 129.1,
129.2, 129.7, 135.9, 138.7 (JC F= 4.2 Hz), 143.0 (JCF = 12.7 Hz), 148.5 (JCF = 255 Hz), 150.4, 154.7
ppm. FTIR (CHCl3):3692.5, 3066.1, 3024.3, 2241.4, 1890.7, 1607.9, 1578.6 cm-1. LRMS (70 eV)
m/z (%): 265 (100) [M+], 237 (35), 208 (47), 199 (19), 170 (24), 84 (51). HRMS (EI-TOF) m/z: [M]+
Calcd for C16H8FNO2 265.0539; Found 265.0540.
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8-(Benzyloxy)-2-oxo-5-phenyl-2H-chromene-3-carbonitrile (3gc). (123.6 mg; 35%). Amorphous
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solid. H NMR (CDCl3, 400 MHz):  5.23 (s, 2H), 7.16-7.45 (m, 12H), 8.20 (s, 1H) ppm. C NMR
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(CDCl3, 100 MHz): = 71.6, 103.1, 113.8, 116.2, 119.1, 126.1, 127.4, 128.4, 128.6, 128.8, 129.0,
129.8, 134.8, 135.7, 136.6, 145.2, 145.6, 150.9, 155.8 ppm. FTIR (CHCl3):3694.5, 3592.2, 3065.8,
3025.2, 228.2, 1746.5, 1596.9, 1564.2 cm-1. LRMS (70 eV) m/z (%): 353 (1.8) [M+], 263 (1.7), 177
(4.4), 151 (3.0), 91 (100). HRMS (EI-TOF) m/z: [M]+ Calcd for C23H15NO3 353.1052; Found
353.1064.
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ASSOCIATED CONTENT
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Copies of 1H NMR and C NMR spectra for compounds 1g, 2g and 3. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: fgarcia@ipna.csic.es; dtejedor@ipna.csic.es
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the Spanish Ministerio de Economía y Competitividad (MICINN) and
the European Regional Development Fund (CTQ2011- 28417-C02-02). L. C. thanks the Spanish MEC
for a FPI grant.
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