TETRAHEDRON
LETTERS
Tetrahedron Letters 44 (2003) 8383–8386 Pergamon
Monoalkylation of dihydroxycoumarins via Mitsunobu
dehydroalkylation under high intensity ultrasound. The synthesis
of ferujol
Giancarlo Cravotto,
a,
* Stefano Chimichi,
b,
* Bruna Robaldo
a
and Marco Boccalini
b
a
Dipartimento di Scienza e Tecnologia del Farmaco, Universita ` di Torino, via Giuria 9, 10125 Torino, Italy
b
Dipartimento di Chimica Organica ‘U. Schiff’, Universita ` di Firenze, via della Lastruccia 13, I -50019 Sesto F.no, Firenze, Italy
Received 17 July 2003; revised 8 September 2003; accepted 16 September 2003
Abstract—Monoalkylation of natural dihydroxycoumarins was carried out by Mitsunobu dehydroalkylation under sonochemical
conditions. Aesculetin (6,7-dihydroxycoumarin) was selectively alkylated in good yield with prenyl alcohols at position 7, as
clearly shown by NOESY experiments; though less selectively, position 7 was also the most reactive in daphnetin (7,8-dihydroxy-
coumarin). The synthesis of the phytoestrogen ferujol is also reported for the first time.
© 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The Mitsunobu reaction
1
has been exploited in the
chemistry of a wide range of naturally occurring com-
pounds like carbohydrates,
2
peptides,
3
terpenes
4
and
others with formation of ethers, esters and new CC
bonds.
5
The nucleophilic substitution of an alcohol
group mediated by the triaryl- or trialkyl-phosphine/
dialkyl azodicarboxylate redox system is widely used to
prepare biologically active compounds with interesting
applications in solid phase synthesis
6
and combinatorial
chemistry.
7
The regio- and stereoselectivity of the reac-
tion have been thoroughly reviewed.
5
Although its reac-
tion mechanism with saturated alcohols is well known,
uncertainty lingers on the factors that govern its course
when allyl or prenyl alcohols are employed. Although
allylic alcohols react according to the normal S
N
2
mechanism, some instances are found in the literature
of an S
N
2 mechanism.
5
The reaction normally proceeds
with inversion of configuration at the carbon atom
bearing the hydroxy group, yet complete retention of
configuration has been observed in the lactonization of
hindered alcohols.
8
As regards regioselectivity, Ko
9
found that with syn -2,3-dihydroxy esters only the -
hydroxy group reacted. On the other hand, with 1,3-
dicarbonyl compounds, the reaction yields mixtures of
C - and O -alkylation products because the enolate
charge is delocalized.
10
It is well known that 4-hydroxy-
coumarin usually gives O -alkylation products.
11
In a
recent paper
12
we compared the outcomes of the reac-
tion under conventional and sonochemical conditions,
showing that high intensity ultrasound influences only
slightly the regioselectivity, while markedly increasing
reaction rates and yields. Our preliminary data,
13
fur-
ther developed by Appendino,
14
indicate that the Mit-
sunobu reaction affords an easy way to perform a
differential esterification of alcoholic and phenolic
hydroxy groups.
We have now found that the Mitsunobu reaction allows
a differential etherification of the phenolic groups in
dihydroxycoumarins. Although phenol etherification
has been widely exploited,
15
to the best of our knowl-
edge, this result has never been published.
Scheme 1. Reagents and conditions :(i ) ROH, PPh
3
, DIAD,
THF, )))) 45 min or stirring at 20°C for 5–8 h; (ii ) Ac
2
O,
pyridine.
Keywords : dihydroxycoumarins monoalkylation; high intensity ultra-
sound; Mitsunobu dehydroalkylation; ferujol synthesis.
* Corresponding authors. Tel.: +39 (0)55 457 3537; fax: +39 (0)55 457
3568; e-mail: stefano.chimichi@unifi.it
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.114