primary alcoholic group. Esters of lipophilic acids have been
prepared to favor the utilization of hydroxytyrosol derivatives
in nonaqueous media.7–9 In addition, the synthesis of esters
of polyphenolic acids such as caffeic acid9 and gallic acid,9
the latter exerting an HIV-1 reverse transcriptase inhibitor
activity, have been described.
Scheme 2
Surprisingly, despite the potential interest from a biological
point of view of hydroxytyrosol derivatives bearing substit-
uents on the aromatic ring, no examples of selective
functionalization in this position have been reported. On the
other hand, such a functionalization might provide a con-
venient access to new classes of bioactive molecules.
Thus, as part of a program devoted to the chemical
valorization of widespread diffused molecules in renewable
sources, we became interested in the preparation of arylated
hydroxytyrosols via Suzuki-Miyaura cross-coupling. Clearly,
Suzuki-Miyaura cross-coupling with this electron-rich hin-
dered substrate is expected to be more difficult compared to
electron-poor unhindered substrates.
Compound 5 was in turn prepared from hydroxytyrosol in
80% overall yield via selective protection with dimethyl
carbonate/catalytic sulfuric acid11 and 2,2-dimethoxypropane/
catalytic camphorsulphonic acid.12 Acetonide derivatives
2a-c were chosen as substrates because our attempts to
prepare the halogenated derivatives from the carbonate ester
4 met with failure. For example, treatment of 4 with I2,
Ag2SO4 in EtOH at room temperature10a for 24 h afforded
an o-iodo monoethyl ether derivative (13% yield) as the sole
isolable product.
In the present paper, we report a general, high-yielding
method for the palladium-catalyzed arylation of the
2-chlorohydroxytyrosol derivative 2c with arylboronic
acids (Scheme 1).
The reaction of 2-iododerivative 2a with phenylboronic
acid in toluene at 80 °C was initially examined as the model
system. Good to excellent results were obtained using
“classical” precatalyst systems such as Pd(PPh3)4 (Table 1,
Scheme 1
Table 1. Palladium and Phosphine Ligands in the
Suzuki-Miyaura Cross-Coupling of 2a with Phenylboronic
Acida
entry
precatalyst system (equiv)
yieldb (%) of 3a
1
2
3
4
Pd(PPh3)4 (0.04)
75
91
95
93
Pd(OAc)2 (0.04)/PPh3 (0.16)
Pd2(dba)3 (0.02)/Xphos (0.04)
Pd2(dba)3 (0.02)/Sphos (0.04)
a Reactions were carried out on a 0.2 mmol scale, under argon, in 1.4
mL of toluene at 80 °C for 0.5 h using 1 equiv of 2a, 1.5 equiv of
phenylboronic acid, 3 equiv of K3PO4. b Yields are given for isolated
products.
Cross-coupling experiments were carried out with the
2-iodo, 2-bromo, and 2-chloro derivatives 2a-c,10 which
were prepared in 94, 90, and 85% yields, respectively, via
halogenation of 5 under the conditions shown in Scheme 2.
entry 1) or Pd(OAc)2/PPh3 (Table 1, entry 2). Utilization of
Pd2(dba)3 in the presence of Xphos or Sphos13,14 (Table 1,
entries 3 and 4) did not afford yields significantly higher
than those obtained with Pd(OAc)2 and PPh3.
However, these conditions were quickly determined to be
unsuitable for the development of a general arylation method.
Indeed, when the procedure was extended to other arylbo-
ronic acids, only p-tolylboronic acid afforded the corre-
sponding hydroxytyrosol derivative in 79% yield with
(7) For enzyme-catalyzed esterification, see: (a) Buisman, G. J. H.; Van
Helteren, C. T. W.; Kramer, G. F. H.; Veldsink, J. W.; Derksen, J. T. P.;
Cuperus, F. P. Biotechnol. Lett. 1998, 20, 131. (b) Torres de Pinedo, A.;
Penalver, P.; Perez-Victoria, I.; Rondon, D.; Morales, J. C. Tetrahedron
2005, 61, 7654. (c) Trujillo, M.; Mateos, R.; Collantes De Teran, L.;
Espartero, J. L.; Cert, R.; Jover, M.; Alcudia, F.; Bautista, J.; Cert, A.;
Parrado, J. J. Agric. Food Chem. 2006, 54, 3779. (d) Grasso, S.; Siracusa,
L.; Spatafora, C.; Renis, M.; Tringali, C. Bioorg. Chem. 2007, 35, 137. (e)
Torres de Pinedo, A.; Penalver, P.; Morales, J. C. Food Chem. 2007, 103,
55. (f) Torres de Pinedo, A.; Penalver, P.; Perez-Victoria, I.; Rondon, D.;
Morales, J. C. Food Chem. 2007, 105, 657
.
(8) For Ce(III)-promoted esterification, see: Torregiani, E.; Seu, G.;
Minassi, A.; Appendino, G. Tetrahedron Lett. 2005, 46, 2193
.
(9) For esterification using the Mitsunobu reaction, see: Appendino, G.;
Minassi, A.; Daddario, A.; Bianchi, F.; Tron, G. C. Org. Lett. 2002, 4,
(12) Gambacorta, A.; Tofani, D.; Bernini, R.; Migliorini, A. J. Agric.
Food Chem. 2007, 55, 3386.
3839
.
(10) Compounds 2a-c were prepared according to standard methods
described in the literature. 2a: (a) Wah, S. W. Synth. Commun. 1992, 22,
3215 2b: (b) Bovicelli, P.; Bernini, R.; Antonioletti, R.; Mincione, E.
Tetrahedron Lett. 2002, 43, 5563 2c: (c) Yanhua, Z.; Kazutaka, S.; Hisashi,
Y. Synlett 2005, 2837.
(13) Sphos ) 2-(2′,6′-dimethoxybiphenyl)dicyclohexylphosphine; Xphos
) 2-(2′,4′,6′-triisopropylbiphenyl)dicyclohexylphosphine.
(14) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L J. Am. Chem. Soc.
1998, 120, 9722. (b) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (c) Barder,
T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc.
(11) Bernini, R.; Mincione, E.; Crisante, F.; Fabrizi, G.; Gentili, P.
Tetrahedron Lett. 2007, 63, 7000.
2005, 127, 4685
.
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Org. Lett., Vol. 10, No. 16, 2008