Synthesis of coumarins by ring-closing metathesis using Grubbs' catalyst

Article abstract of DOI:10.1016/S0040-4039(03)00902-X

A novel generally applicable synthesis of coumarins from phenolic substrates utilizing ring-closing metathesis is described. This sequence involves O-allylation of phenols followed by ortho-Claisen rearrangement, subsequent based-induced isomerization affording 2-(1-propenyl)phenols, acylation with acryloyl chloride, and finally ring-closing metathesis (RCM) with Grubbs' second generation catalyst.

Full text of DOI:10.1016/S0040-4039(03)00902-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4199–4201
Synthesis of coumarins by ring-closing metathesis using Grubbs’
catalyst
Tuyen Nguyen Van, Silvia Debenedetti† and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure links 653,
B-9000 Ghent, Belgium
Received 1 April 2003; accepted 5 April 2003
Abstract—A novel generally applicable synthesis of coumarins from phenolic substrates utilizing ring-closing metathesis is
described. This sequence involves O-allylation of phenols followed by ortho-Claisen rearrangement, subsequent based-induced
isomerization affording 2-(1-propenyl)phenols, acylation with acryloyl chloride, and finally ring-closing metathesis (RCM) with
Grubbs’ second generation catalyst. © 2003 Elsevier Science Ltd. All rights reserved.
Coumarins are widespread in nature as physiologically
active constituents of plants.1–3 In addition, coumarin
derivatives have a broad range of applications in the
pharmaceutical, perfume, and cosmetic industries. They
have been used as additives to food and cosmetics,
optical brightening agents and dispersed fluorescent
and laser dyes. The diverse biological activities of cou-
marins is well known as anticoagulants, antithrom-
botics,4 antimicrobial,2c antibacterial activities,2
anticancer3 and anti-HIV activity.5 The interesting bio-
logical activity of these coumarins made these com-
pounds attractive targets in organic synthesis. Several
synthetic strategies for the synthesis of coumarins have
already been developed. Coumarins can be synthesized
by the Perkin reaction,6a Pechmann reaction6b or by
Knoevenagel condensation of salicylaldehydes with
Scheme 1.
* Corresponding author.
† On leave from the University of La Plata, Argentina.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00902-X

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T. Nguyen Van et al. / Tetrahedron Letters 44 (2003) 4199–4201
malonic acid,7,8 malonic esters,8,9 cyanoacetic esters10a
or Meldrum’s acid.10b Recently, the Wittig reaction in
N,N-diethylaniline was also conveniently applied for
the synthesis of coumarins.11 However, all reported
methods have disadvantages (harsh reaction condition,
low yield, difficult purification), making the develop-
ment of a new reliable high-yielding method for the
synthesis of coumarins an important subject.
Recently, the improved highly reactive ruthenium-based
olefin metathesis catalyst (Grubb’s second generation
catalyst) was found to catalyze the reaction more
efficiently.18c,d Several practical methods for the inter-
molecular cross-metathesis and intramolecular ring-
closing metathesis using ruthenium alkylidenes have
been reported yet.16,18b,18d These results could be
applied for the intramolecular ring-closing metathesis
of a,b-unsaturated esters 5a–e affording coumarins.
In continuation of our longstanding interest in cou-
marin chemistry, in which several new coumarins have
been isolated from medicinal plants and some of them
were synthesized,12 a new method for the synthesis of
coumarins by ring-closing metathesis using Grubbs’
catalyst was developed.
Accordingly (Scheme 1), 2-(1-propenyl)aryl acrylates
5a–d were treated with 5 mol% of Grubbs’ second
generation catalyst in dichloromethane at reflux for 24
h giving rise to coumarins 6a–d in 70–90% yield.19 Via
this synthesis of coumarins by RCM, the natural
product ayapin 6c, isolated from Pterocaulon
polystachium,12c P. virgatum,12e P. serrulatum,20a Den-
drobium densiflorum,20b and the natural 5,8-dimethoxy-
coumarin 6d from Artemisia carvifolia,20c were
synthesized in 83 and 72% yield, respectively. However,
compound 5e, when treated with the same catalyst in
dichloromethane under reflux for 44 h, afforded cou-
marin 6e only in 70% yield. In order to improve the
yield of coumarin 6e, the reaction conditions were
modified (Scheme 2). In a first step, aryl acrylate 5e was
treated with 1 equiv. of Ti(OiPr)4 in dichloromethane
under reflux for 1 h, then 5 mol% of Grubbs’ second
generation catalyst was added and reflux was continued
for 4 h, to give coumarin 6e21 in very good yield (93%).
Probably, the use of Ti(OiPr)4 could diminish the com-
plexation between the carboxylic oxygen and the ruthe-
nium catalyst.
The starting materials, phenols 1a–e, were alkylated by
treatment with allyl bromide in the presence of potas-
sium carbonate in acetone at reflux for 12 h affording
the corresponding allyl ethers 2a–e in very good yield
(Scheme 1).13 ortho-Claisen rearrangement of com-
pounds 2a–e by heating in DMF (v/v 1/1) at 190°C
gave the corresponding phenols 3a–e.13 In the case of
compound 2d, the reaction product was obtained as a
result of ortho-Claisen rearrangement (63%) and para-
Claisen rearrangement (30%). Allylaryl ether 2e was
heated in DMF at 190°C for 36 h. Only 40% conver-
sion to 2-allylphenol 3e was obtained under this condi-
tion, but the neat ether 2e rearranged to 2-allylphenol
3d at 290°C almost exclusively.14 Isomerization of phe-
nols 3a–e was carried out by treatment with potassium
tert-butoxide in THF15 for 12 h at room temperature to
give phenols 4a–e in 90–98% yield as a mixture of E-
and Z-isomer (about 4:1). In the case of 2-allylphenol
derivative 3d, compound 4d was obtained in only 5%
yield. In order to improve the yield of the reaction, the
reaction mixture was refluxed in THF for 24 h yielding
2(1-propenyl)phenol 4d in 90% yield as the E-isomer,
exclusively. Acylation of phenols 4a–e was carried out
by treatment with acryloyl chloride in dichloromethane
in the presence of triethylamine, affording unsaturated
aryl esters 5a–e in 81–93% yield.16
In conclusion, ring-closing metathesis using second gen-
eration Grubbs’ ruthenium catalyst as a new method
for the synthesis of coumarins was developed.23
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1
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the synthesis of coumarins using RCM. In a personal
communication, Professor R. Grubbs informed us that
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tion in Pure and Applied Chemistry (2003). The latter
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complimentary to the results of Grubbs group.