Anodic oxidation: An attractive alternative to CAN-mediated cleavage of para-methoxyphenyl ethers

Article abstract of DOI:10.1002/ejoc.200900262

para-Methoxyphenyl (PMP) ether is a very convenient protecting group for the alcohol function; however, its cleavage requires strong oxidative conditions. In this field, the use of powerful eerie ammonium nitrate has been widely described, despite the fac

Full text of DOI:10.1002/ejoc.200900262

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900262
Anodic Oxidation: An Attractive Alternative to CAN-Mediated Cleavage of
para-Methoxyphenyl Ethers
Carine Vaxelaire,[a] Florence Souquet,[a] Marie-Isabelle Lannou,[a] Janick Ardisson,*[a] and
Jacques Royer*[a]
Keywords: Oxidation / Electrochemistry / Protecting groups / Cleavage reactions
para-Methoxyphenyl (PMP) ether is a very convenient pro- strates. In this paper, a new anodic oxidation method for the
tecting group for the alcohol function; however, its cleavage
requires strong oxidative conditions. In this field, the use of
powerful ceric ammonium nitrate has been widely described,
despite the fact that its strong nature results in the formation
of degradation products in acid- or oxidation-sensitive sub-
cleavage of para-methoxyphenyl ethers in weakly basic me-
dium is reported. This process is an attractive alternative to
circumvent the use of ceric ammonium nitrate.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
yield as that reported (91%). In fact, compound 3 was iso-
lated in 20–80% yield, the rest of the mass balance account-
ing mainly for degradation products.
para-Methoxyphenyl (PMP) ether has emerged as a very
interesting and useful protecting group for the alcohol func-
tion, as this ether is stable under strongly acidic or basic
conditions and is specifically cleaved under oxidative condi-
tions. Moreover, this ether possesses unique properties in
inducing high stereoselectivities in enantioselective reac-
tions. For instance, according to Corey et al.,[1] asymmetric
dihydroxylation of homoallylic alcohols has been shown to
provide enantiopure diols with good enantiomeric excesses
(96%ee) exclusively when the hydroxy group is protected as
a PMP ether. When the PMP group was replaced by any
other protecting group, for example, the para-methoxyben-
zoate group, a severe loss of enantioselectivity was ob-
served. Thus, the PMP group is a powerful hydroxy protect-
ing group; however, its synthetic usefulness relies on the
availability of a general and efficient cleavage method. Al-
though ceric ammonium nitrate (CAN) remains the most
widely used reagent for this purpose,[2] in our case some
difficulties were encountered.
Scheme 1. Procedure outlined by Tietze for the preparation of com-
pound 3.
Exploitation of the oxidizing properties of CAN for syn-
thetic purposes remains limited due to a striking lack of
selectivity in the cleavage of PMP ethers with regard to
other hydroxy protecting groups. This drawback is particu-
larly well evidenced in reactions involving acid-sensitive
moieties, as the mechanism of CAN-induced removal of
PMP ethers involves the liberation of hydronium ions in the
reaction medium. This can be circumvented by the use of
bases like pyridine or an aqueous solution of sodium hydro-
gen carbonate,[4] but even under these conditions, CAN still
leads to partial decomposition of material. Finally, from an
In the course of our work, we have been interested in the
preparation of alcohol 3 according to a procedure reported
by Tietze (Scheme 1).[3] In our hands, the CAN cleavage
step unfortunately failed to give alcohol 3 within the same
[a] Laboratoire de Synthèse et Structure de Molécules d’Intérêt
Pharmacologique UMR 8638-CNRS Université Paris De- experimental point of view, purified compounds systemati-
scartes
cally reveal a red colour, which implies that trace amounts
of cerium salts still remain.
However, despite the disadvantages mentioned above, to
date only a few alternative methods have been reported and
are anecdotally used, among these are: lithium in liquid
Faculté des Sciences Pharmaceutiques et Biologiques
4, av. de l’Observatoire, 75270 Paris cedex 06, France
Fax: +33-1-43291403
E-mail: janick.ardisson@parisdescartes.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900262.
3138
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Eur. J. Org. Chem. 2009, 3138–3140

Alternative to CAN-Mediated Cleavage of para-Methoxyphenyl Ethers
ethylamine,[5] silver oxide/nitric acid in dioxane[6] silver(II) Table 1. Oxidative cleavage of primary and secondary alkyl para-
methoxyphenyl ethers.
dipicolinate–H2O complex in a MeCN/H2O/MeOH mix-
ture[7] and silver oxide/2,6-pyridine dicarboxylic acid in
MeCN/H2O.[8] Thus, in case of highly functionalized sub-
strates and more particularly in the field of total synthesis,
selective and efficient cleavage of PMP protecting groups
has turned out to be of primary interest.
Electrochemical deprotection methods are scarcely re-
ported[9] while generally providing mild conditions respec-
tive of many sensitive functional groups. In 2005, our group
described the deprotection of N-para-methoxyphenylamines
(N-PMP) by anodic oxidation.[10] To date, very few papers
deal with the anodic cleavage of the carbon–oxygen bond
in PMP ethers. The first example concerns diaryl ethers.[11]
The reaction, conducted in methanol, provides bis(acetal)s.
This method is directed by p-methoxy substitution.
The second example deals with the deprotection of para-
methoxyphenyl pyranosides.[12] In this particular case, the
removal of anomeric PMP groups was described without
investigation of the scope of the reaction and, as such, can-
not be extended to the standard regeneration of aliphatic
alcohols. Noteworthy, experiments have only been carried
out on analytical scale (0.006 to 0.139 mmol). Thus, the
lack of preparative scale methods is obvious.
In this paper, a preparative anodic cleavage of primary
and secondary alkyl para-methoxyphenyl ethers is reported.
[a] Reactions were conducted on 3.75 mmol at C = 15 m.
[b] Yields of isolated product. [c] Reaction was conducted at 1.55 V
vs. SCE and at C = 1.5 m. [d] Reaction conducted at E = 1.4 V.
Results and Discussion
In order to establish a general method, the reaction was
first carried out on PMP ether 4 derived from 2-phenyle-
thanol. The results are presented in Table 1. All the experi-
ments were conducted in a separated cell at a controlled
potential (i.e, vs. saturated calomel electrode, SCE) at plati-
num electrodes. The very first assay was performed at a con-
centration of 1.5 m in a 9:1 mixture of acetonitrile/water
Scheme 2. General procedure for the oxidative cleavage of alkyl
para-methoxyphenyl ethers.
Compared to AO, model compound 4 was easily depro-
at room temperature, and the oxidation potential was fixed tected by using CAN, despite a lower yield,[15] showing that
at a constant value of 1.55 V (Table 1, Entry 1).[13] Under CAN-mediated cleavage is more degradative (Table 1, En-
these conditions, alcohol 5 was obtained with a satisfactory try 1).
77% yield within 1 h. It was then observed that the use of
Various diols bearing both a PMP and an acid-sensitive
a saturated aqueous solution of sodium hydrogen carbonate protecting group (tert-butyldimethylsilyl 6, tetrahydropyran
instead of water had a beneficial effect, giving a cleaner 8 and dimethylacetonide 2, 10) evidenced selective PMP
reaction. In parallel, increasing the potential to 1.7 V re- ether cleavage under buffered-anodic oxidation conditions
sulted in an increased yield. Finally, it was found possible (Table 1, Entries 3–6). Interestingly, the protocol for AO
to work under more concentrated conditions (from 1.5 to was successfully applied to ether 2 and target alcohol 3 was
15 m) without loss of yield, thus giving access to a prepar- easily regenerated in high yield (Table 1, Entry 5). In con-
ative method. Finally, the combination of the three above- trast, the CAN-mediated cleavage of ethers 2 and 6
mentioned conditions led to excellent results (92% yield; (Table 1, Entry 5 and 3, respectively) resulted in degrada-
Table 1, Entry 2) and was elected as a standard for the tion products, whereas 8 (Table 1, Entry 4) was cleanly
cleavage of a set of PMP ether compounds (Scheme 2).[14]
cleaved. Finally, anodic oxidation gave the best yield in the
The course of the electrolysis can be monitored by TLC selective removal of the PMP group of 12 bearing a base-
or by measurement of residual intensity (the reaction was sensitive pivaloate function (Table 1, Entry 7).
stopped when the intensity reached less than 5% of its ini-
tial value).
Anodic oxidation using NaHCO3 as buffer is suitable to
the cleavage of PMP ethers in the presence of acid- and
In order to establish a comparison, most relevant sub- base-sensitive substrates. Consequently, a wide range of hy-
strates were submitted to both anodic oxidation (AO) and droxy protecting groups is compatible with buffered-anodic
buffered CAN-mediated cleavage of PMP ethers.
oxidation method.
Eur. J. Org. Chem. 2009, 3138–3140
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3139

C. Vaxelaire, F. Souquet, M.-I. Lannou, J. Ardisson, J. Royer
SHORT COMMUNICATION
The reaction was further checked on oxidation sensitive oxidation-sensitive functions are tolerated. Finally, this
substrates. Enyne 14 was successfully converted into alcohol method can be easily carried out by using basic electro-
15 (Table 1, Entry 8), and neither decomposition nor allylic chemical equipment and on preparative scale.
oxidation was observed. In the same manner, the PMP
Supporting Information (see footnote on the first page of this arti-
group of substrate 16 was cleanly cleaved in the presence
of a para-methoxybenzyl (PMB) group (Table 1, Entry 9).
However, in this latter case, the potential was fixed at 1.4 V
to avoid PMB group oxidation. At the opposite, under
CAN-mediated cleavage conditions, enynol 15 was isolated
in low yields from 14, whereas PMP ether function of 16
was selectively cleaved in the presence of PMB ether.
Finally, cleavage of the secondary para-methoxyphenyl
ether group of 18 was also carried out, leading to menthol
(19; Table 1, Entry 10) in satisfactory, although unopti-
mized, yield.
As a conclusion, in all cases studied, anodic oxidation
provided the required alcohols in better yields than buffered
CAN-mediated reaction. These examples have efficiently
demonstrated that the anodic oxidation reaction was highly
selective, contrary to CAN-induced cleavage of PMP ethers,
which has exhibited side reactions such as cleavage of acid-
labile functions. Moreover, contrary to the CAN-mediated
reaction, the AO process is highly reproducible.
cle): Detailed procedures and characterization data for ethers and
alcohols illustrated in Table 1.
Acknowledgments
This work was supported by the Centre National de la Recherche
Scientifique (CNRS) and the University Paris Descartes. We thank
M. Pulicani for kind loan of integrator AMEL 731.
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The mechanism of the anodic oxidation is similar to the
one assumed for CAN-mediated cleavage of para-meth-
oxyphenyl ethers. In both cases, stepwise oxidation of the
para-methoxyphenyl function led to the formation of
quinone together with the expected aliphatic alcohol. It is
worth specifying that the reaction was complete when a
quantity of electricity of 2.2 Fmol–1 was delivered into the
reaction medium; thus the coulometric yield is close to the
theoretical amount of electricity (2 F/mol).
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Conclusions
[13] Voltammogram of the substrate revealed an oxidation wave
around 1.4 V.
In summary, we have demonstrated that primary and sec-
ondary alkyl para-methoxyphenyl ethers can easily be
cleaved by anodic oxidation. The reaction is rapid (0.5 to
1 h) and constitutes an attractive, nondegradative alterna-
tive to CAN-mediated cleavage, which provides desired
alcohols in a cleaner manner and with more reproducible
yields. Moreover, this is also an original orthogonal process
for the selective deprotection of para-methoxyphenyl pro-
tecting groups, as a wide range of acid-, base- and even
[14] The anodic oxidation of compound 4 was also done under con-
stant current conditions (120 mA) and alcohol 5 was obtained
with a good yield of 70%. The elaboration of a general method
is currently under investigation in our laboratory.
[15] Two batches of commercial CAN were used for testing. Slight
differences in yields were observed, depending on the batch
used.
Received: March 11, 2009
Published Online: May 13, 2009
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