Remarkable effect of 2,2′-bipyridyl: Mild and highly chemoselective deprotection of methoxymethyl (MOM) ethers in combination with TMSOTf (TESOTf)-2,2′-bipyridyl

Article abstract of DOI:10.1039/b907910f

The remarkable effect of 2,2′-bipyridyl led to the successful development of the mild and highly chemoselective deprotection method of methoxymethyl (MOM) ethers using the combination of TMSOTf (or TESOTf) and 2,2′-bipyridyl; this method can be applied to the direct conversion of the MOM group to other ethereal protective groups (e.g. benzyloxymethyl) with the corresponding alcohols. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b907910f

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Remarkable effect of 2,20-bipyridyl: mild and highly chemoselective
deprotection of methoxymethyl (MOM) ethers in combination
with TMSOTf (TESOTf)–2,20-bipyridylw
Hiromichi Fujioka,* Ozora Kubo, Kento Senami, Yutaka Minamitsuji
and Tomohiro Maegawa
Received (in Cambridge, UK) 21st April 2009, Accepted 15th May 2009
First published as an Advance Article on the web 11th June 2009
DOI: 10.1039/b907910f
The remarkable effect of 2,20-bipyridyl led to the successful
development of the mild and highly chemoselective deprotection
method of methoxymethyl (MOM) ethers using the combination
of TMSOTf (or TESOTf) and 2,20-bipyridyl; this method can
be applied to the direct conversion of the MOM group to other
ethereal protective groups (e.g. benzyloxymethyl) with the
corresponding alcohols.
method, we attempted the deprotection of MOM ether under
the same conditions. The reaction, however, did not proceed
and only formation of the collidinium intermediates was
observed (Scheme 1).
The unsuccessful deprotection of MOM ether may be
explained by the fact that the lower steric crowding of the
collidinium salts makes the intermediates stable even in the
presence of water. After a detailed investigation, we have
found the remarkable effect of 2,20-bipyridyl to promote
the deprotection of MOM ethers under mild conditions. In
addition, this method can be applied to the direct replacement
of MOM ether with other ethereal protective groups.
We initiated our study by examining the effect of silyl
triflates during the deprotection of n-decylmethoxymethyl
ether (1a) with 2,4,6-collidine. TMSOTf and TESOTf showed
similar results and could form the collidinium intermediate.
We then chose less expensive TMSOTf for further optimiza-
tion and next investigated a variety of pyridine derivatives
more bulky than 2,4,6-collidine for the efficient removal of the
MOM ether. The results after a 24 h treatment of the inter-
mediate with water and Et2O12 (except entries 6 and 7) are
shown in Table 1.
Protection of the hydroxy group is essential for multi-step
syntheses of natural products as well as complex molecules.
Also, the mild removal of the protective group is important in
the synthesis of complex and especially sensitive molecules.1
Among a number of protective groups of the hydroxy function
developed so far,2 methoxymethyl (MOM) ether is one of the
most extensively utilized because the MOM group can be
tolerated under strong basic conditions as well as weak acidic
conditions.2 Tetrahydropyranyl (THP) ether, a similar type of
protective group, is also commonly used, but the introduction
of THP ether onto chiral, secondary and tertiary alcohols
leads to diastereo-mixtures which make isolation or NMR
analysis complicated.2 Many methods have been developed to
remove the MOM group under acidic conditions such as using
protic acids,3 Lewis acids,4 Lewis acid-thiol,5 boron halides,6
and other reagents7 in protic media or aprotic media.
However, some methods have been restricted to utilization
only for molecules without acid-sensitive functions because of
their strong acidity. A few deprotection methods under mild
conditions using ethylene glycol or propylene glycol,8 or
The reaction of 1a using 2,6-lutidine (entry 1) and 2,4,6-
collidine (entry 2) afforded a trace amount of product (2a) and
the pyridinium intermediates as a major product. The more
bulky 2,6-di-tert-butylpyridine and 2,6-dichloropyridine also
afforded a trace amount of the product and mainly the starting
material and byproduct12 (entries 3 and 4). The deprotection
proceeded efficiently when 2-chloropyridine was used and the
corresponding alcohol (2a) was obtained in 77% yield
(entry 5). The use of 2-phenylpyridine also resulted in similar
yield of 2a (75%) although a longer reaction time was
necessary (72 h) (entry 6). Finally, to our surprise, the reaction
with 2,20-bipyridyl gave the best result and 2a was obtained in
85% yield for 6 h reaction (entry 7).
9
CBr4–PPh3 have been reported although there are some
problems due to the necessity of a high reaction temperature
or limitation of substrates.
We have developed chemoselective deprotection of acetals
by the combination of triethylsilyl triflate (TESOTf)–2,4,6-
collidine in the presence of ketals.10 The reaction proceeded via
the collidinium intermediates under mild and non-acidic
conditions, without affecting acid-labile functional groups, to
produce aldehydes. This deprotection is also applicable to the
removal of THP ethers affording the parent alcohols under the
same conditions (Scheme 1).11 For further application of this
Graduate School of Pharmaceutical Sciences, Osaka University,
1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.
E-mail: fujioka@phs.osaka-u.ac.jp; Fax: +81 668798229;
Tel: +81 668798225
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for the product compounds. See
DOI: 10.1039/b907910f
Scheme 1 The reactions of THP and MOM ethers with TESOTf and
2,4,6-collidine.
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Table 1 Effect of pyridinesa
Table 2 Deprotection of MOM ether by TMSOTf (TESOTf)–2,20-
bipyridyla
Entry
Pyridine
t/h
Yield (%)
Entry
Substrate
Silyl triflate
t/h
Yield (%)
1
2
3
4
5
6
7
2,6-Lutidine
2,4,6-Collidine
24
24
24
24
24
72
6
Traceb
Traceb
Trace
3
77
75
1
2
TMSOTf
TESOTf
6
6
85 (2a)
90 (2a)
2,6-Di-tert-butylpyridine
2,6-Dichloropyridine
2-Chloropyridine
2-Phenylpyridine
2,20-Bipyridyl
3
4
TMSOTf
TESOTf
2
2
91 (2b)
81 (2b)
85
a
Reaction conditions: 1a (1.0 equiv.), TMSOTf (2.0 equiv.), the
pyridine (3.0 equiv.) in CH2Cl2 (0.2 M) at 0 1C for 0.5 h then H2O
and Et2O were added and stirred at rt. The formation of pyridinium
salt was detected by TLC analysis.
5
6
TMSOTf
TESOTf
1
2
99 (2c)
92 (2c)
b
7
8
TMSOTf
TESOTf
10
7
81 (2d)
55 (2d)
To explore the scope and limitation of this novel MOM
deprotection method, we conducted the reactions of diverse
MOM-protected alcohols under the optimized conditions
{TMSOTf (TESOTf)–2,20-bipyridyl in CH2Cl2}13 (Table 2).
Primary, secondary and tertiary aliphatic MOM ethers were
easily converted to the corresponding alcohols in good to high
yields within several hours (Table 2, entries 1, 3 and 5). The use
of TESOTf instead of TMSOTf is also applicable for the
removal of MOM ethers (entries 2, 4 and 6). The presence of
olefin, acetoxy, benzoyloxy and benzyloxy functions does not
cause any hindrance and the corresponding alcohols were
obtained in good yields (entries 7–14). It is noteworthy that
this method can be applied to the deprotection of MOM ethers
without affecting acid-sensitive functional groups such as
triphenylmethyl (Tr) and tert-butyldimethylsilyl (TBS) groups
(entries 15–18) since it is known that some conventional
methods for the removal of the MOM ether caused the
undesirable concomitant deprotection of such acid-sensitive
functionalities because of their acidity.4b,d,14 Intriguingly, the
reaction of the phenolic MOM ether did not proceed at all and
no formation of the pyridinium salt was observed when
TESOTf was used (entry 20) while the use of TMSOTf
afforded deprotected product in 19% yield (entry 19).
9
(R = Ac) 1e
(R = Bz) 1f
(R = Bn) 1g
(R = TBS) 1h
(R = Tr) 1i
TMSOTf
TESOTf
TMSOTf
TESOTf
TMSOTf
TESOTf
TMSOTf
TESOTf
TMSOTf
TESOTf
5
5
5
5
5
5
5
4
4
89 (2e)
91 (2e)
93 (2f)
86 (2f)
86 (2g)
87 (2g)
88 (2h)
91 (2h)
92 (2i)
82 (2i)b
10
11
12
13
14
15
16
17
18
2.5
19
TMSOTf
24
19 (2j)
20
TESOTf
24
n.r.c
a
Reaction conditions: 1 (1.0 equiv.), TMSOTf or TESOTf (2.0 equiv.),
2,20-bipyridyl (3.0 equiv.) in CH2Cl2 (0.2 M) at 0 1C for 0.5 h then H2O
and Et2O were added and stirred at rt. The reaction was conducted
b
c
in CH2Cl2 (0.5 M). No reaction.
Scheme 2 Selective deprotection of the aliphatic MOM group in the
Conventional methods could simultaneously cleave both the
aliphatic and phenolic MOM ethers4a,b,d,7b,e and some
methods were reported for the preferential cleavage of the
phenolic MOM ether to that of the aliphatic one.7c,d There-
fore, we examined the selective deprotection between aliphatic
and phenolic MOM ethers using TESOTf (Scheme 2). Only
the aliphatic MOM ether was cleaved under the stated condi-
tions and the corresponding MOM protected aliphatic alcohol
was obtained in 85% yield.15
presence of phenolic MOM group.
The plausible mechanism of this reaction is shown in
Scheme 3. The quantitative formation of the intermediate of
the parent alcohol (2) indicated that silyl triflates should
selectively coordinate to the outer oxygen (next to the methyl
group) of the MOM ether (1) to afford the intermediate (A).16
The attack of H2O on A would give the hemiacetal which
decomposes to the corresponding alcohol (2). The suitable
bulkiness of the pyridine derivative seems to be necessary for
the smooth hydrolysis (Table 1) since the less steric hindered
Scheme 3 Plausible mechanism of deprotection of MOM ether by
TMSOTf–2,20-bipyridyl.
2,4,6-collidine could not form the hemiacetal and bulky
pyridine derivatives such as 2,6-di-tert-butylpyridine and
2,6-dichloropyridine led to undesirable side reactions.
The smooth conversion of A to 2 using 2,20-bipyridyl
compared to 2-phenylpyridine, although they two seem to
ꢀc
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4430 | Chem. Commun., 2009, 4429–4431

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Scheme 4 Direct conversion to other methylether groups from MOM
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12 Bis(n-decyloxy)methane was obtained in the absence of Et2O as a
major byproduct. In the case of entries 3 and 4, the same byproduct
was obtained even in the presence of Et2O.
13 The typical procedure is as follows; TMSOTf (or TESOTf)
(0.28 mmol, 2.0 equiv.) was added dropwise to a solution of
MOM ether (1) (0.14 mmol, 1.0 equiv.) and 2,20-bipyridyl
(0.42 mmol, 3.0 equiv.) in CH2Cl2 (0.7 mL, 0.2 M) at 0 1C under
N2. The reaction mixture was stirred for 0.5 h at 0 1C, H2O
(2.0 mL) and Et2O (2.0 mL) were added to the solution and stirred
at rt. The mixture was extracted with CH2Cl2. The organic layer
was washed twice with 3.5% HCl aq. and with sat. NaHCO3 aq.
The combined organic layer was dried over Na2SO4, filtered, and
evaporated in vacuo. The residue was purified by SiO2 column
chromatography to give pure 2.
14 I2–MeOH has been reported to be applicable not only to the
deprotection of MOM group (ref. 7e) but also to the deprotection
of trityl ether: (a) J. L. Wahlstrom and R. C. Ronald, J. Org.
Chem., 1998, 63, 6021; (b) A. R. Vaino and W. A. Szarek, Synlett,
1995, 1157.
15 Only one method has been reported which indicated the similar
reactivity to our result; see, ref. 7f.
16 The intermediate A is too unstable to be isolated and only
detected on TLC analysis whereas the intermediate from 1a and
2,4,6-collidine is stable and isolable. The NMR spectrum of the
collidinium intermediate is available in ESIw.
ether.
have a similar moderate steric hindrance, might suggest that
the nitrogen atom on the adjacent pyridine ring helps to bring
the H2O close to the acetal carbon and make the nucleophilic
attack by H2O easier, which resulted in the acceleration of
hydrolysis. The electron density of the pyridine ring might also
affect the hydrolysis.
As further application of this method, we planned the direct
replacement of the MOM ether by other methylether type
protective groups. The replacement of the protective group to
another one with different properties is sometimes an impor-
tant strategy especially for total syntheses. Normally, such a
transformation needs two steps to be converted into other
protective groups, removal and reprotection, which may affect
other functions within the molecules. We have reported the
efficient formation of mixed acetals from acetals11 and it might
be applicable to the replacement of MOM ethers by other
ethereal protective groups when the corresponding alcohol is
used instead of H2O. Consequently, the direct conversion of
the MOM ether (1i) to benzyloxymethyl (BOM) ether success-
fully proceeded in 73% yield in one-pot using 5 equiv. of
benzyl alcohol as a nucleophile. This is also applicable for the
conversion to 2-(trimethylsilyl)ethoxymethyl (SEM) ether
from 1i in 78% yield (Scheme 4). These results also indicated
the selective coordination of TMSOTf to the outer oxygen
(next to methyl group) of the MOM ether (Scheme 3).
In conclusion, we developed a novel and efficient method for
the deprotection of MOM ether under mild conditions. The use
of 2,20-bipyridyl is effective and significantly accelerated the
reaction progress. The present method is applicable for sub-
strates bearing acid-sensitive functions which remain intact.
Further application of this method provides an easy and direct
replacement of the MOM ether to BOM and SEM ethers in a
one-pot procedure. The present method will open a new aspect
of deprotection method of MOM ethers in organic syntheses.
This work was supported by a Grant-in-Aid for Scientific
Research (B) and for Scientific Research for Exploratory
Research from Japan Society for the Promotion of Science
(JSPS).
Notes and references
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Chem. Commun., 2009, 4429–4431 | 4431