Tetrahedron Letters 48 (2007) 1241–1245
Fast deprotection of phenoxy benzyl ethers in
transfer hydrogenation assisted by microwave
Monica Quai,a,* Claudio Repetto,b Walter Barbagliaa and Enzo Ceredaa
aChemistry Research Centre, Boehringer Ingelheim Italia, Via Lorenzini 8, Milano, Italy
bOrganic Chemistry Department, Rotta Research Laboratorium, Via Valosa di Sopra 7, Monza, Italy
Received 31 October 2006; revised 5 December 2006; accepted 11 December 2006
Available online 8 January 2007
Abstract—Phenoxy benzyl ethers are easily and quickly deprotected in the presence of ammonium formate and microencapsulated
Pd(0)EnCat with the assistance of microwave irradiation. This procedure can be applied in the presence of other functional groups
as well. The described protocol is particularly convenient for the preparation in a parallel and automatic fashion of libraries of com-
pounds possessing a phenol type moiety.
Ó 2006 Elsevier Ltd. All rights reserved.
The development of protecting groups and the conse-
quent deprotection is a field of still increasing interest
to successfully address more and more complex mole-
cules. Among the protecting groups, the benzyl (Bn) is
of widespread use in masking functional groups such
as alcohols, phenols, acids and amines.1,2 In medicinal
chemistry the benzyloxy groups are often the precursors
of phenols which are present as essential pharmaco-
phore in many well known classes of compounds
endowed with pharmacological activity, such as
catecholamines, DOPA, b-adrenergics and serotonine
derivatives.3 Although well spanned methods to accom-
plish the deprotection of phenoxy benzyl ethers do exist,
an affordable, clean and fast procedure amenable to
automation would be valuable in the preparation of
libraries of compounds possessing a free hydroxy func-
tion of phenol type. Microwave (MW) assisted organic
synthesis is now a well established technique and almost
all chemical transformations can be carried out effi-
ciently and in extremely shortened times.4,5 Only a few
microwaves enhanced hydrogenations are reported as
gaseous hydrogen is not much compatible with MW
technique mainly for safety reasons. To overcome these
drawbacks dedicated reactors have been recently devel-
oped6 or, as a preferred option, hydrogen donors such
as formate salts, cyclohexene and analogues are used7,8
according to transfer hydrogenation conditions. The
debenzylation processes both under traditional condi-
tions and with microwave assistance are carried out in
the presence of Pd/C as a catalyst and this causes some
trouble when used in the automated preparation of
libraries. First, a safe handling is hampered by its pyro-
phoric nature. Second, nano particles of palladium, in
many cases not compatible with biological screening,
still remain into the crude product after filtration.
We report here a new method for the O-debenzylation
of phenoxy compounds well suited for the rapid prepa-
ration of substances for pharmacological screening. To
the best of our knowledge O-debenzylation in transfer
hydrogenation assisted by microwaves has been
reported only for aliphatic alcohols.9 We now expand
the scope of the process to aromatic substrates of phenol
type and along with the MW assistance accomplished in
a sequential automated fashion we introduce the use of
microencapsulated Pd(0)EnCatTM as a catalyst which
couples a safe and easy handling with a decreased prod-
uct contamination (less than 10 ppm) caused by metal
leaching.10–13
To explore fast and set up a suitable method as a model
compound we selected 1-(4-benzyloxyphenyl)-pipera-
zine, hydrochloride (1). It contains the target benzyl
ether, it has an amine function which allows for a rapid
detection in LC/MS of the formed compounds, it has a
chromophore well suited for detection and quantisation
Keywords: Transfer hydrogenation; Microwave chemistry; Debenzyl-
ation; Microincapsulated catalysts.
*
Corresponding author. Tel.: +39 02 5355254; fax: +39 02 5355457;
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.041