Ytterbium triflate promoted coupling of phenols and propiolic acids: Synthesis of coumarins

Article abstract of DOI:10.1016/j.tetlet.2016.05.087

Coumarins are a well-known class of natural occurring and semi-synthetic products with reported important and effective pharmacological activities. In this Letter an improved method for the chemical synthesis of such compounds is described. Coumarins have been obtained in good to excellent yields under microwave irradiation and solvent-free conditions in a short time from differently substituted phenols and propiolic acids used as starting materials in the presence of Yb(OTf)₃ hydrate 10% mol as the catalyst.

Full text of DOI:10.1016/j.tetlet.2016.05.087

Accepted Manuscript
Ytterbium triflate promoted coupling of phenols and propiolic acids: Synthesis
of coumarins
Serena Fiorito, Francesco Epifano, Vito A. Taddeo, Salvatore Genovese
PII:
S0040-4039(16)30620-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.087
TETL 47706
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
6 April 2016
22 May 2016
23 May 2016
Please cite this article as: Fiorito, S., Epifano, F., Taddeo, V.A., Genovese, S., Ytterbium triflate promoted coupling
of phenols and propiolic acids: Synthesis of coumarins, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.05.087
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Ytterbium triflate promoted coupling of phenols and
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S. Fiorito, F. Epifano, V.A. Taddeo, S. Genovese
COOH
OH
O
O
Yb(OTf)3
MW, 2 min.
+
R1
R1
R2
R2
Yb+3 = 91 - 98%, Sc+3, La+3, Ce+3, or Gd +3 = < 25 %

1
Tetrahedron Letters
Ytterbium triflate promoted coupling of phenols and propiolic acids: synthesis of
coumarins
Serena Fiorito, Francesco Epifano, Vito A. Taddeo, Salvatore Genovese*
Dipartimento di Farmacia, Università “G. d’Annunzio” of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti Scalo (CH), Italy; Email: s.genovese@unich.it
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Coumarins are a well-known class of natural occurring and semi-synthetic products with
reported important and effective pharmacological activities. In this paper an improved method
for the chemical synthesis of such compounds is described. Coumarins have been obtained in
good to excellent yields under microwave irradiation and solvent-free conditions in a short time
from differently substituted phenols and propiolic acids used as starting materials in the presence
of Yb(OTf)3 hydrate 10 % mol as the catalyst.
Available online
Keywords:
Catalysis
2009 Elsevier Ltd. All rights reserved.
Coumarins
Lanthanides
Microwave irradiation
Ytterbium triflate
Coumarins are a well-known group of widely naturally
occurring and semi-synthetic heterocyclic compounds.1
Coumarin (2H-chromen-2-one) is the archetype and most
representative molecule of the whole class. It was first extracted
from Dypterix odorata Wild., commonly known as “tonka bean”,
and subsequently extensively studied for its pharmacological
properties.2 Other relevant examples are represented by auraptene
from Citrus spp., endowed with anti-inflammatory and cancer
chemopreventive properties,3 dicoumarol, from mouldy and wet
clover hay, used for several years as an anti-coagulant,4 osthol
from the Chinese medicinal plant Cnidium monnieri (L.) Cusson
ex Juss., currently subject of deep investigation for its wide array
of pharmacological activities,5 scoparone from Artemisia
(H2SO4,15 HClO4,16 Nafion-H,17 zeolites,18 Amberlyst-15,19
montomorillonite clays, SBA-15,21 and different Lewis acids22) in
stoichiometric or catalytic amounts have been used to this
purpose. Unfortunately several of these processes suffer major or
minor drawbacks such as harsh reaction conditions, low yields,
tedious work-up procedures, lack of regiochemical control in the
ring closure step, use of hazardous reagents like highly corrosive
acids, lack of recyclability of catalysts, and co-occurrence of
several side reactions. In light of their important pharmacological
potentialities, the development of novel synthetic schemes of
differently substituted coumarins is a noteworthy and useful task
in organic, medicinal, and combinatorial chemistry and
represents a field of research of current and growing interest.
scoparia
Waldst., possessing immunomodulatory and
During the last thirty years, triflates of metals belonging to the
lanthanide series have been seen as effective water tolerant
recyclable Lewis acids. Such rare earth metals have been
discovered to catalyse several carbon–carbon and carbon–
heteroatom bond formation reactions providing the desired
products in excellent yields by means of a green chemical
approach.23 In the frame
vasorelaxant effects,6 and warfarin (marketed as Coumadin ®),
commonly used in therapy for its anti-coagulant properties.7 In
general coumarin derivatives exert a broad spectrum of
pharmacological activities acting as anti-depressant, anti-
microbial, anti-oxidant, anti-inflammatory, anti-nociceptive, anti-
cancer, anti-viral, and anti-coagluant agents. The beneficial
effects of natural and synthetic coumarins have been recently
comprehensively reviewed.8 In addition coumarin derivatives
have been largely investigated for their optical properties as laser
dyes, fluorescent probes and whiteners, optical chromophores,
and solar energy collection.9
we report in this
manuscript that the coumarin ring can be efficiently obtained by
Yb(OTf)3 hydrate promoted condensation of propiolic acids and
differently substituted phenols under microwave irradiation
(MW) and solvent-free conditions (Figure 1). Indeed Yb(OTf)3
has been already employed to this purpose performing the
Pechmann condensation between differently functionalized
phenols and β-ketoesters, but the process required high
temperatures and, although stated as recyclable, no experimental
The coumarin nucleus has been built by several routes,
representing “classic” processes of the organic synthetic
chemistry like Pechmann, Perkin, Knoevenagel, Wittig and
Reformatski reactions in acidic or basic media.10 Numerous
heterogenous and homogenenous bases (e.g. secondary and
tertiary amines,11-12, hydrotalcites,13 inorganic oxides14) or acids

2
Tetrahedron
Blank experiments have been performed without catalyst also for
details about the recovery of the catalyst have been given.
all the entries listed in the Table 1, each time providing yields < 5
%, estimated by 1H NMR analysis of the raw reaction mixture. In
no cases intermediate alkynoic esters, deriving from the coupling
of the phenol group with the carboxyl acid, have been detected.
Morevoer potentially air sensitive moieties like ortho-diphenols
(entries 4 and 5), remained unaffected under the employed
experimental conditions. Yb(OTf)3 has been recovered by
filtration under vacuum from every reaction as described above.
The catalyst could be reused to perform further steps without
significant loss of its activity. For example the reaction leading to
umbelliferone (entry 10) was accomplished five additional times
with the recycled Yb(OTf)3 providing the desired adduct in 93%,
93%, 95%, 92%, and 90% yields. The same process was
accomplished with other lanthanide triflates, namely Sc+3, La+3,
Ce+3, and Gd+3. Poor conversion of starting phenols have been
observed in every case providing yields lower than 25 %,
Moreover such a reaction is limited to the synthesis of 4-
methylcoumarins.24
COOH
OH
O
O
Yb(OTf)3
+
MW, 2 min.
R1
R1
R2
R2
Figure 1. General synthetic route to substituted coumarins by
Yb(OTf)3 promoted coupling of phenols and propiolic acids
The use of alkynoic acid for coumarin synthesis is known in the
literature to be a valid alternative and has been performed using
different transition metals (e.g. FeCl3/AgOTf,25 Pd(OAc)2,26
Hf(OTf)4,27 Pt-based reagents28). However the application of
MW-irradiation and Yb(OTf)3 to promote the title condensation
is reported herein for the first time to the best of our knowledge.
1
estimated by H NMR analysis of the raw reaction mixture. The
more catalytic efficiency of Yb+3 may be explained by the fact
that it is the “hardest” and thus most oxophilic metal centre due
to its smaller ionic radius in the lanthanide series.29 A plausible
mechanism of the herein described process is similar to that
depicted by Kitamura and coworkers.26 Briefly it can be
hypothesized that Yb+3 first catalyzes the esterification of
propiolic acid by the phenol function, followed by an
intramolecular Friedel-Craft acylation and cyclization yielding
the 2-pyrone ring, through an enhancement of reactivity of the
triple bond by the coordination of the Lewis acid to the alkynoic
ester as outlined in Scheme 1.
First tests have been performed using phenol (1.0 mmol) and
propiolic acid (1.1 mmol), in the presence Yb(OTf)3 5% mol as
the catalyst that were let to react in a round bottom flask at 120
°C for 30 min. under solvent-free conditions. The progress of the
reaction was monitored by thin layer chromatography (TLC).
After the indicated time the complete disappearance of the
starting materials was observed although a very complex not
separable mixture of products have been formed. We then
decided to change parameters affecting the process but all
modifications (e.g. use of solvents like CH2Cl2, CHCl3, EtOAc,
or Et2O, shorter reaction times, lowering temperatures to 60 °C,
increasing catalyst load to 20% mol) proved to be unsuccessful.
In all cases several spots have been detected on TLC or, as
occurring for temperature below 60 °C, no conversion of the
starting materials was observed. We then decided to change
experimental conditions and assay the efficiency of MW
irradiation using the same substrates. After several attempts in
terms of reaction times (1 - 15 min.) and MW power values
ranging from 100 W to 800 W (1 bar), the best conditions were
established to be an MW power of 200 W (equivalent to a
temperature of 80° C), a reaction time of 2 min., and the
presence of Yb(OTf)3 hydrate 10% mol. Adoption of these
parameters led a complete conversion of the starting materials to
a pure product. The crude mixture resulting from this step was
diluted with Et2O, the catalyst recovered by filtration, the filtrate
washed twice with a 5% NaHCO3 solution, dried over MgSO4
and evaporated to dryness under vacuum to provide the desired
Yb+3
O
OH
OH
O
O
Yb+3
R
R
O
O
R
Scheme 1
As a conclusion, we have demonstrated that differently
substituted phenols and propiolic acids undergo an efficient
condensation reaction under the catalysis of Yb(OTf)3 hydrate
providing differently functionalized coumarins using MW
irradiation under solvent-free conditions in very good yields. The
simple work-up procedure, complete recovery and recyclability
of the catalyst, and mild experimental conditions render our
methodology a valid and alternative contribution in the field of
the coumarin ring synthesis, favourably comparing to the already
described processes. Further investigations into the scope and
other applications of Yb(OTf)3 promoted reactions are now in
progress in our laboratories and will be reported in due course.
1
coumarin (entry 1) in 95% yield. H and 13C NMR analysis and
comparison with a commercially available sample confirmed the
structure of this latter compound. It is noteworthy that shorter
reaction times resulted in an incomplete formation of coumarin
while increasing time respect to that indicated resulted in a huge
degradation of the final product as revealed by TLC analysis.
Loading of the catalyst less than 10 % mol provided no
satisfactory results in terms of yields, while an increase up to
20% mol did not significantly affect recorded yields.
Encouraged by results obtained using phenol and propiolic acid
we applied MW irradiation to differently substituted phenols and
alkynoic acids and the corresponding coumarins have been
synthesized in very good yields as summarized in the Table 1.
Acknowledgments
Financial support from Università “G. d’Annunzio” of Chieti-
Pescara is gratefully acknowledged (Fondi FAR 2015).
Differently substituted phenols with electron withdrawing and
electron donor substituents attached to the benzene ring and
alkynoic acids reacted to the same extent furnishing selectively
the desired compounds in yields ranging from 91 % to 98 %.
References and notes
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3
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4
Tetrahedron
Table 1. Yb(OTf)3 promoted synthesis of coumarins by MW irradiation. A comparison with yields obtained with other lanthanides
(Ln = Sc+3, La+3, Ce+3, Gd+3) is reported.
Ent
ry
Ar-OH
Alkynoic acid
Product
Yield (%)a
[Yb+3]
[Ln+3]
O
O
1
2
3
Phenol
Propiolic
93
92
93
12- 23
HO
O
O
Resorcinol
Orcinol
Propiolic
9 - 23
HO
O
O
Propiolic
11 -17
OH
H3CO
O
O
4
5
3-Methoxycathecol
Pyrogallol
Propiolic
Propiolic
93
98
12 - 17
7 - 13
OH
HO
HO
O
O
O
O
6
7
Phloroglucinol
m-Cresol
Propiolic
Propiolic
96
96
11 - 23
11 - 25
OH
O
O
O
O
O
O
8
9
4,7-Dihydroxycoumarin
4-Methylumbelliferone
Propiolic
Propiolic
94
91
11 - 16
13 - 19
OH
O
O
O
O
O
O
O
O
10
11
Umbelliferone
Propiolic
Propiolic
93
94
9 - 14
7 - 13
O
O
-Naphtol

5
F
O
O
O
O
12
2-Fluorophenol
Propiolic
94
11 - 18
O2N
13
14
15
3-Nitrophenol
4-Chlorophenol
Phenol
Propiolic
Propiolic
98
97
94
12 - 18
11 - 19
14 - 24
O
O
Cl
O
O
Phenylpropiolic
Ph
O
F
O
O
16
2-Fluorophenol
Phenylpropiolic
97
11- 19
Ph
O
O2N
Phenylpropiolic
Phenylpropiolic
17
18
3-Nitrophenol
98
91
9 - 13
9 - 14
Ph
O
O
4-Chlorophenol
Cl
Ph
O
O
19
20
Phenol
2-Butynoic
2-Butynoic
93
94
11 - 18
10 - 19
F
O
O
2-Fluorophenol
O2N
O
O
2-Butynoic
2-Butynoic
21
22
3-Nitrophenol
93
92
11 - 15
7 - 12
O
O
4-Chlorophenol
Cl
aYields of pure isolated products, characterized by 1H NMR and 13C NMR

6
Tetrahedron
19. De La Hoz, A.; Moreno, A.; Vazquez, E. Synth. Lett. 1999, 608-610.
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7
1) A new method for the synthesis of coumarins is
reported
2) A new application of ytterbium triflate catalysis
3) First example of a coupling between phenols and
alkynoic acids promoted by microwave irradiation