Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2739–2742
Selective ortho-cleavage of methoxymethyl- and 4-methoxybenzyl
ethers
John M. Keith*
Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego 92121, USA
Received 1 December 2003; revised 5 February 2004; accepted 10 February 2004
Abstract—Iodine in methanol has been found to be an effective catalyst system for the cleavage of alkoxymethyl ethers. This catalyst
system is particularly useful for the selective removal of ortho-methoxymethyl- and ortho-(4-methoxybenzyl) ethers in the presence of
their para-counterparts. Further investigation of various metal salts in methanol for their ability to cleave alkoxymethyl ethers
revealed high-valent salts as effective catalysts, presumably through the release of small quantities of HCl.
Ó 2004 Elsevier Ltd. All rights reserved.
In the field of organic synthesis, mild removal of pro-
tecting groups is often necessary, especially for complex
or sensitive substrates. Molecules bearing multiple
identical protecting groups have additional challenges
associated with them if a selective deprotection is nec-
essary later in the synthesis. In the course of our
research, we needed to developa method to selectively
remove a methoxymethyl (MOM) groupfrom the
2-position of bis-MOM protected 5-substituted-2,4-di-
hydroxyacetophenones (Scheme 1). We felt such a
selective deprotection should be possible, as other pro-
tecting groups have been cleaved from similarly func-
tionalized scaffolds.1 Ideally, the method used would be
mild, easy to set up/work up, and not require special
handling techniques or anhydrous solvents. We were
attracted to the work by Szarek whereby his group
utilized 1 wt % of iodine in methanol to cleave silyl
ethers, 4-methoxybenzyl ethers (PMB), and acetonides
to their respective alcohols.2 Subsequent research dem-
onstrated that the I2/MeOH catalyst system is capable of
removing tetrahydropyranyl3 and trityl4 protecting
groups as well as mediate transesterification.5 Addi-
tionally, I2/MeOH was also used to selectively cleave
aliphatic silyl ethers in the presence of their phenolic
counterparts in high yield.6
O
O
R
R
MOMO
OMOM
MOMO
OH
Scheme 1.
products.7 Acid generation in the liquid phase
is also suggested as I2/MeOH solutions have
been shown to be mildly acidic.6 Additionally, only
alcohols bearing an a-hydrogen to the –OH group
are effective solvents for this reaction.3 Presumably,
oxidation of the alcoholic solvent by iodine at this
position is necessary to generate catalytic amounts of
HI.
While I2/MeOH had been used to cleave acetonides, we
were unsure whether this reagent system would be
effective at the removal of the more robust methoxy-
methyl ethers. When we first utilized this reagent sys-
tem8 we were delighted to observe selective deprotection
of 5-chloro-2,4-dihydroxyacetophenone at the 2-
position9 in 76% yield (Table 1, entry 1). The reaction
proceeded at room temperature in 8 h using reagent
grade methanol without additional purification or dry-
ing. Longer reaction times resulted in greater amounts
of di-deprotected material. Encouraged by this result,
other substrates were subjected to the reaction condi-
tions in an effort to elucidate the scope of the observed
selectivity. Acids and amides (entries 2A and 3)10;11 were
well tolerated, giving useful yields (70–94%) of mono-
deprotected products. MOM esters were cleaved along
Iodine has been shown to react with methanol in
the gas phase, generating hydrogen iodide and other
Keywords: Selective cleavage; MOM; PMB; Iodine; Methanol; Solvo-
lysis.
* Tel.: +1-858-784-3275; fax: +1-858-450-2049; e-mail: jkeith@prdus.
jnj.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.039