Tetrahedron Letters
Mild deprotection of PMB ethers using tert-butyl bromide
b,
Nicolas Rival a, Arantxa Albornoz Grados b, Lucie Schiavo b, Françoise Colobert b, , Gilles Hanquet
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a SINTEF Material and Chemistry, Forskningsveien 1, NO-0314 Oslo, Norway
b Laboratoire de Synthèse et Catalyse associé au CNRS, ECPM, Université de Strasbourg, 25 rue Becquerel, 67087 Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient and high yielding method for the cleavage and scavenging of p-methoxybenzyl protecting
group of several alcohols using tert-butyl bromide in refluxing acetonitrile is described. Under these mild
conditions other protecting groups such as acid sensitive allyl, benzyl, and Me3CPh2Si ethers, or
isopropylidene acetals were unchanged. Interestingly, a selective alkoxy-PMB cleavage was observed
in the presence of a PMB phenoxy ether.
Received 6 August 2015
Revised 16 October 2015
Accepted 19 October 2015
Available online 20 October 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
PMB ether deprotection
Tert-butyl bromide
Selective deprotection
4-Methoxybenzyl ether
Introduction
cleavage conditions. PMB ethers are generally stable under mild
acidic conditions but can be cleaved in the presence of strong
One important tool in the total synthesis of natural products is
the mild and selective cleavage of hydroxyl protecting group.
According to the functional group diversity of such molecules,
cleavage conditions should be as mild as possible and orthogonal
to other hydroxyl protecting groups. The para-methoxybenzyl
ether (PMB) is one of the most common hydroxyl protecting
groups since it is generally stable toward a large panel of reaction
conditions and can be selectively cleaved.1 Numerous methodolo-
gies exist for the selective removal of the PMB group including
oxidative condition with 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ),2 which has been then optimized using NBS or co-oxidants
such as HClO4, HIO4, HNO3, FeCl3, and Mn(OAc)3 to minimize the
use of DDQ.3 Ceric ammonium nitrate (CAN) can also be used for
the oxidative cleavage of PMB ethers.4 These oxidative conditions
led to a major drawback with the formation of side products such
as 4-anisaldehyde or dichlorodicyanohydroquinone. Later on, ano-
dic oxidation5 and photoredox catalysis6 have been used as other
oxidative cleavages of PMB ethers. Reductive cleavage of PMB
ethers was alternatively described using the NaCNBH3–BF3ÁEt2O7
system but gave rise to another side product, 4-methylanisole. This
method is also not suitable for compounds with reducible and acid
sensitive functional groups. A lot of effort has been put on the
combination of a Lewis acid and a soft nucleophile, such as
acids in certain conditions. For instance, acetic acid at 90 °C,9 10%
trifluoroacetic acid in dichloromethane,10 trifluoroacetic, methane-
sulfonic, or triflic acid with 1,3-dimethoxybenzene in toluene,11 or
TFA-anisole in dichloromethane,12 or triflic acid with N-methyl-p-
toluenesulfonamide, cleaved efficiently PMB ethers. Functionalized
resins such as sulfonamide-functionalized (‘safety-catch’) could
also be used.13 Iodohydric acid-mediated deprotection of PMB
ethers has also been described with extension to other
alkoxymethyl.14 Just recently, a combination of Ag(I)SbF6 (5 mol
%) and 1,3,5-trimethoxybenzene (0.5 equiv),15 POCl3 (0.5 equiv)
in dichloroethane,16a oxalyl chloride in dichloroethane,16b and
proton-exchanged montmorillonite16c was reported as useful
reagents for the deprotection. In case of acidic catalysis, if the
conjugate is a weak nucleophile, scavengers have to be used to
avoid production of dimers and polymeric products resulting
from the self-condensation of the released PMB cation.17 This can
be bypassed if strong nucleophiles such as ClÀ are formed during
the protection simplifying the work up procedure.8e,16 Very
recently, a self-cleaving PMB deprotection catalyzed by FeCl3 was
described, leading when quantitative, to the mother alcohols
without purification.18
During the course of our studies toward the synthesis of the
polyol part of Amphidinol-3,19 we carried out the reduction of
AlCl3–dimethylaniline,8a
MgBr2–Me2S,8b
CeCl3Á7H2O–NaI,8c
hydroxysulfoxide 1 into the corresponding sulfide 2 using
SnCl4–PhSH,8d ZrCl4–CH3CN,8e Ce(OTf)3,8f or TMSI-TPP,8g as mild
tert-butyl bromide20 in refluxing chloroform (Scheme 1). To our
surprise, the dihydroxysulfide 2 was isolated as a major product
of this reaction, in which the reduction of the sulfinyl group
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Corresponding authors. Fax: +33 368852742.
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.