Metal-free, Br?nsted acid-mediated synthesis of coumarin derivatives from phenols and propiolic acids

Article abstract of DOI:10.1016/j.tetlet.2016.06.039

A novel synthesis of coumarin derivatives by Br?nsted acid-mediated condensation and intramolecular cyclization of phenols and propiolic acids was reported. This transformation requires the use of TfOH in place of a conventional metal mediator, and it occurs under mild conditions and provides rapid access to coumarin derivatives in good yields.

Full text of DOI:10.1016/j.tetlet.2016.06.039

Accepted Manuscript
Metal-Free, Brønsted Acid-Mediated Synthesis of Coumarin Derivatives from
Phenols and Propiolic Acids
Hyuck Choi, Jaehyun Kim, Kooyeon Lee
PII:
S0040-4039(16)30708-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.039
TETL 47766
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 April 2016
6 June 2016
10 June 2016
Please cite this article as: Choi, H., Kim, J., Lee, K., Metal-Free, Brønsted Acid-Mediated Synthesis of Coumarin
Derivatives from Phenols and Propiolic Acids, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.
2016.06.039
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Tetrahedron Letters
Metal-Free, Brønsted Acid-Mediated Synthesis of Coumarin Derivatives from
Phenols and Propiolic Acids
Hyuck Choia, Jaehyun Kima, and Kooyeon Leea,b, 
a
Department of Bio-Health Technology, Kangwon National University, Chuncheon 200-701, Republic of Korea
Institute of Bioscience and Biotechnology, Kangwon National University, Chuncheon 200-701, Republic of Korea
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel synthesis of coumarin derivatives by Brønsted acid-mediated condensation and
intramolecular cyclization of phenols and propiolic acids was reported. This transformation
requires the use of TfOH in place of a conventional metal mediator, and it occurs under mild
conditions and provides rapid access to coumarin derivatives in good yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Courmarin
Brønsted Acid
Trifluoromethanesulfonic acid
Condensation
Cyclization
———
 Corresponding author. Tel.: +82-33-250-6477; fax: +82-33-250-6470; e-mail: lky@kangwon.ac.kr

2
Tetrahedron Letters
Heterocyclic compounds are extremely significant in
numerous natural products and biological active
pharmaceuticals.1 Accordingly, much effort has been devoted to
construct skeletons of heterocyclic molecules.2 In particular,
coumarins are the basic structural units present in various natural
products with a wide range of biological activities.3 Recently,
they have been used as effective organic electroluminescent
materials.4 Because of their many applications, numerous
synthetic methods such as Perkin, Pechmann, Knoevenagel,
Reformatsky, and Wittig reactions have been developed for
obtaining different coumarin derivatives.5 Among these, the most
commonly used reaction is the Pechmann reaction, which
involves condensation of phenols and β-ketoesters (Scheme 1, eq.
1).6 However, Pechmann reaction has certain drawbacks as well;
e.g., requirement of the excessive amount of acid and, in certain
instances, generation of by-products such as chromone.
Therefore, more efficient transition-metal-mediated methods for
the preparation of coumarins were developed.7 However, most of
these reactions require an iodoarene precursor such as
iodophenol; they also generate halide waste because of the
activation of the C‒X bond by the transition metal. Trost et al.
developed an atom-economic synthesis of coumarins via
palladium-catalyzed C‒H bond functionalization of phenols with
propiolic acid, leading to C‒C bond formation (eq. 2).8 In another
report, coumarins were prepared by metal-promoted alkyne
activation.9 Recently, Lee and co-workers reported a metal-free
method of coumarins via Brønsted acid-mediated condensation
of allenes (eq. 3).10 In this work, we describe metal-free synthesis
of coumarin derivatives by Brønsted acid-mediated condensation
of phenols with propiolic acids (eq. 5).
Temp.
(℃)
Time
(h)
Yield b
(%)
Entry Acid(equiv.)
Solvent
1
HCl (2.0)
Chlorobenzene
80
6
0
CH3CO2H
(2.0)
2
3
Chlorobenzene
Chlorobenzene
80
80
6
6
0
0
CF3CO2H
(2.0)
4
5
TsOH (2.0)
MsOH (2.0)
Chlorobenzene
Chlorobenzene
80
80
6
6
4
13
6
7
8
TfOH (2.0)
TfOH (2.0)
TfOH (1.0)
Chlorobenzene
Chlorobenzene
Chlorobenzene
80
100
80
3
1
3
75
84(76)c
11
9
TfOH (2.0)
TfOH (2.0)
TfOH (2.0)
TfOH (2.0)
DCE
CH3CN
Toluene
THF
80
80
80
80
3
3
3
3
37
0
10
11
12
38
0
a Reaction Conditions: p-cresol (1a, 1.0 mmol), propiolic acid (2a, 0.5 mmol),
solvent (3.0 mL), under a nitrogen atmosphere.
b Yields are based on 2a, determined by crude 1H NMR using
dibromomethane as the internal standard.
c Isolated yield.
In order to evaluate the applicability of this transformation, we
investigated the reaction of propiolic acid 2a with phenols
bearing various functional groups. Unsubstituted phenol 1a
afforded coumarin derivative 3a in 76% yield after 2 h (Table 2,
entry 1). Introduction of a methyl substituent at the ortho position
resulted in 74% yield of the corresponding derivative 3b (entry
2). When the methyl substituent was introduced at the meta
position, 7-methylcoumarin 3ca and 5-methylcoumarin 3cb were
produced in 90% and 10% 1H NMR yields, respectively, and 3ca
was isolated in 75% yield (entry 3). The reaction of p-
methylphenol 1d and 3,5-dimethylphenol 1e also proceeded in
good to excellent yields to form the corresponding derivatives
(entries 4 and 5). Introduction of a phenyl group at the para
position produced derivative 3f in 54% yield (entry 6). When the
substituent is a methoxy group, the yields diminished, and 7-
methoxycoumarin 3ga was found to be the major product in the
reaction of m-methoxyphenol (entries 7 and 8). Introduction of an
electron-withdrawing group such as chloride at the ortho or para
position resulted in low yields (13% and 14%, respectively;
entries 9 and 11). However, when the chloride was introduced in
the meta-position, the reactivity increased, and, regioselectively,
7-chlorocoumarin (3j) was formed (entry 10). When resorcinol
(1l) was used, 7-hydroxycoumarin (3la) and 5-hydroxycoumarin
(3lb) were obtained in 81% and 5% isolated yields, respectively
(entry 12). The reactions of 1-naphthol (1m) and 2-naphthol (1n)
Scheme 1.
In order to determine the optimal conditions, the reaction
wasperformed in chlorobenzene at 80 C in the presence of a
o
Brønsted acid. The use of 2 equiv of HCl, acetic acid, or TFA
was not effective (Table 1, entries 1-3), whereas addition of
TsOH or MsOH produced small amounts of the desired product
(Table 1, entries 4 and 5). Conducting the reaction at 80 oC for 3
h in the presence of 2 equiv of TfOH afforded product 3a in 75%
1H NMR yield (Table 1, entry 6). On increasing the reaction
temperature to 100 oC, the desired product was generated in 84%
1H NMR yield and 76% isolated yield (Table 1, entry 7). When
the amount of TfOH was reduced to 1 equiv, the reaction yield
decreased dramatically (Table 1, entry 8). When different
solvents were screened, keeping TfOH as the activating agent,
chlorobenzene was found to be optimal (Table 1, entries 10-12).
afforded
2H-benzo[h]chromen-2-one
(3m)
and
3H-
benzo[f]chromen-3-one (3n), respectively, in good yields (entries
14 and 15). Moreover, the reaction of 5,6,7,8-
tetrahydronaphthalen-1-ol (1o) afforded coumarin derivative 3o
in good yield.
Next, the reactivity of various propiolic acids was investigated
by testing compounds carrying an n-pentyl or a phenyl
substituent at the terminal alkyne carbon. When the n-pentyl
substituent was introduced, the expected coumarin (3pa) and
Table 1. Optimization of reaction conditionsa

chromone (3pb) produced by Fries rearrangement were obtained
in 21% and 23% isolated yields, respectively. The reaction of 3-
phenylpropiolic acid (2c) with 4-methoxyphenol (1h) afforded
coumarin 3qa and chromone 3qb in 48% and 33% yields,
respectively (Scheme 2).
Scheme 3.
In conclusion, this study presents the development of a novel
synthetic method for coumarin derivatives by metal-free,
Brønsted acid (TfOH)-mediated condensation of phenols with
propiolic acids, followed by intramolecular hydroarylation. This
method represents an efficient, rapid, and mild protocol for the
preparation of various coumarin derivatives, which are important
precursors in the synthesis of bioactive compounds.
Acknowledgments
This work was supported by the Human Resource Training
Program for Regional Innovation and Creativity through the
Ministry of Education and National Research Foundation of
Korea (No. 2015H1C1A1035955).
Scheme 2.
In our proposed mechanism, TfOH-mediated condensation of
the two substrates yields intermediate ester 3q that can undergo
an acid-activated intramolecular hydroarylation of the alkyne
moiety generating coumarin 3qa. Chromone 3qb is obtained by
the intramolecular cyclization of ketone intermediate 3q'
produced from the acid-induced Fries rearrangement of
intermediate ester 3q (Scheme 3).
Table 2. TfOH-Mediated Synthesis of Coumarin Derivativesa

4
Tetrahedron Letters
a Reaction Conditions: phenol (1.0 mmol), propiolic acid (2a, 0.5 mmol), solvent (3.0 mL), under a nitrogen atmosphere.
b Isolated yield.

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Graphical Abstract (for review)
Graphical Abstract
Metal-Free, Brønsted Acid-Mediated
Leave this area blank for abstract info.
Synthesis of Coumarin Derivatives from
Phenols and Propiolic acids
Hyuck Choi, Jaehyun Kim, and Kooyeon Lee

*Highlights
Research highlights
►A novel synthesis of coumarins was developed which exploits metal-free condition.
►The method was used to produce a range of coumarins in excellent yields.
►This transformation requires the use of TfOH in place of a conventional metal mediator.
►The mechanism explains Brønsted acid-mediated condensation and intramolecular cyclization.