Efficient and catalytic deprotection of triphenylmethyl ethers with Ce(OTf)4

Article abstract of DOI:10.1016/S0040-4020(01)00616-0

A very simple and efficient method is described for deprotection of trityl, mono and dimethoxytrityl ethers using catalytic amount of ceric triflate in acetonitrile under mild reaction conditions. High reactivity was observed for detritylation of saturated and benzylic ethers and also for structurally different nucleosides.

Full text of DOI:10.1016/S0040-4020(01)00616-0

TETRAHEDRON
Pergamon
Tetrahedron 57 12001) 6805±6807
Ef®cient and catalytic deprotection of triphenylmethyl ethers
with CeꢀOTf)4
Ali Khala®-Nezhadp and Reza Fareghi Alamdari
Department of Chemistry, Faculty of Science, Shiraz University, Shiraz 71454, Iran
Received 9 March 2001; revised 8 May 2001; accepted 31 May 2001
AbstractÐA very simple and ef®cient method is described for deprotection of trityl, mono and dimethoxytrityl ethers using catalytic
amount of ceric tri¯ate in acetonitrile under mild reaction conditions. High reactivity was observed for detritylation of saturated and benzylic
ethers and also for structurally different nucleosides. q 2001 Published by Elsevier Science Ltd.
Ether cleavage is a versatile transformation in organic
chemistry and its importance for the deprotection of the
hydroxyl group especially in pharmaceuticals, drugs and
other ®ne chemicals has attracted the attention of synthetic
chemists. The triphenylmethyl 1trityl) group, as a protecting
group for the 50-OH function of the nucleoside moiety is a
most desirable protecting group due to its stability in
slightly acidic, basic and other reaction conditions as is
widely used in oligodeoxynucleoside synthesis.1 However,
this desirable protecting group has not been applied
frequently for the protection of the 50-OH of nucleosides
due to very severe acidic reaction conditions required for
their deprotection 1e.g. the use of protic acids such as
hydrogen chloride, hydrogen bromide, acetic acid, tri¯uoro-
acetic acid, or basic conditions such as use of sodium in
liquid ammonia).2 Thus, its removal from nucleosides
would cause a cleavage, which is accompanied by
depurination 1glycosidic cleavage).
have reported that SnCl2 is an ef®cient reagent for removal
of the dimethoxytrityl group from protected nucleosides.8
Ceric tri¯ate [Ce1OTf)4]9 is neutral in comparison with wet
CAN and is also readily soluble in organic solvents.10,11
Here, we report that ceric tri¯ate is a convenient catalyst
for deprotection of trityl ethers to their corresponding
hydroxyl compounds 1Scheme 1).
The choice of solvent in deprotection of trityl ethers with
Ce1OTf)4 is important. On the basis of our results which are
shown in Table 1, Ce1OTf)4 acts more ef®ciently in polar
solvents such as CH3CN.
Examination of the results shows that primary and second-
ary, aliphatic and benzylic trityl and dimethoxytrityl ethers
are converted to their corresponding hydroxyl compounds
very easily with a catalytic amount of Ce1OTf)4 in CH3CN
in high yields 1Table 2).
Previously, ZnBr2 in dichloromethane or nitromethane,3 and
dialkylaluminum chloride in a homogeneous phase under
nonpolar and completely aprotic conditions,4 have been
used for detritylation. Recently, the trityl and monomethoxy-
trityl groups were removed from protected nucleosides or
nucleotides by the use of ceric ammonium nitrate 1CAN) in
wet acetonitrile under neutral conditions.5 However these
methods encounter some drawbacks. For example detrityl-
ation under acidic conditions may cause acyl migration for
ester containing compounds6 and cleavage of glycosidic
bond in nucleosides and nucleotides,7 and also reactions
take place in a long time, with low yields of the products
and tedious work-up of the reaction mixture. Recently we
Scheme 1.
Table 1. Effect of different solvents on deprotection of di1p-methoxy-
phenyl)phenylmethylbenzyl ether with catalytic amount of Ce1OTf)4 at
room temperature
Solvent
Time
Yielda 1%)
CH2Cl2
THF
CH3CN
CH3NO2
24 h
18 h
5 min
5 min
10
30
95
93
Keywords: deprotection; trityl ethers; ceric tri¯ate; catalytic amount;
nucleoside.
p
Corresponding author. Tel.: 198-711-2222380; fax: 198-711-2220027;
e-mail: khala®@chem.susc.ac.ir
a
Isolated yield after column chromatography.
0040±4020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd.
PII: S0040-4020101)00616-0

6806
A. Khala®-Nezhad, R. Fareghi Alamdari / Tetrahedron 57 *2001) 6805±6807
Table 2. Deprotection of trityl and dimethoxytrityl ethers with Ce1OTf)4
10.1 equiv.) in CH3CN at room temperature
Entry Substrate
Product
Time
1min.)
Yielda
1%)
Scheme 2.
Table 3. Deprotection of 50-tritylated nucleosides with Ce1OTf)4
10.1 equiv.) in CH3CN at room temperature
Substrate
Producta
Time 1min)
Yieldb 1%)
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
1.5 h
45 min
1 h
30 min
10 min
1 h
885
958
905
9213
9613
895
938
1g
2g
30 min
a
The products were isolated and identi®ed by comparison with authentic
samples.
Isolated yields after column chromatography.
b
and electron-withdrawing groups such as ±NO2, decrease
the activity of trityl ethers in deprotection reactions 1Table
2, entry 7).
aIsolated yield after column chromatography.
bDMTˆDi1p-methoxyphenyl)phenylmethyl: 1p-MeC6H4)2PhC±.
An interesting feature of this procedure is the conversion of
50-tritylated nucleosides to the corresponding nucleosides
with a catalytic amount of Ce1OTf)4 1Scheme 2, Table 3).
Trityl ethers are more stable than dimethoxytrityl 1DMT)
ethers and in all cases in our studies their less reactivity,
longer reaction times, and mostly lower yields have been
observed 1Table 2, entries 1,2). Primary benzylic and satu-
rated trityl ethers are more reactive than secondary aliphatic
and benzylic trityl ethers 1Table2, entries 5,10-2,4).
Our results show that the rate of detritylation is much faster
than those reported by CAN. Moreover, no depurination and
any side reactions were observed. We found that the feasi-
bility of deprotection by use of Ce1OTf)4 depends upon the
stability of the resultant carbocation. At the same tempera-
ture, deprotection of 50-O-dimethoxytrityladenosine 11a,
Table 3) is faster than deprotection of 50-O-trityladenosine
12b, Table 3). This is because the dimethoxytrityl cation is
more stable than trityl cation.
Substituted groups on the benzene ring affect the reactivity
of the substrates against the deprotection reaction. Electron-
donating groups such as ±OCH3, increase 1Table 2, entry 6),
Scheme 3.

A. Khala®-Nezhad, R. Fareghi Alamdari / Tetrahedron 57 *2001) 6805±6807
6807
A detritylation mechanism is proposed by using tritylated
1.3. General procedure for removal of trityl, mono-
methoxytrityl, and dimethoxytrityl group from
protected nucleosides
alcohols 1Scheme 3). An essential step involves oxidation of
trityl ether ROCPh3 to the corresponding cation radical
while reduction of Ce1IV) to Ce1III) takes place.12
The protected nucleoside 11 mmol) in wet acetonitrile
130 ml) was treated with a catalytic amount of Ce1OTf)4
173.6 mg, 0.1 mmol) at 258C for 10±90 min. the solvent
was removed under reduce pressure and the residue puri®ed
on silica column, ®rst washed with ether to removed tri-
phenylmethanol, then eluting with ethyl acetate±methanol
11:1) to give the product. The product were isolated and
identi®ed by comparison with authentic samples.5,8,14
Ce1OTf)4 seems to be a more reliable and more ef®cient
reagent than protic acids and other reagents previously
used for the deprotection of trityl ethers.
1. Experimental
Chemicals were either prepared in our laboratories or were
purchased from Fluka, Merck, and Aldrich Chemical
Companies. Products were characterized by comparison of
their physical data with those of authentic samples. All
yields refer to isolated products. The purity determination
of the substrates and the reaction monitoring were accom-
plished by TLC on silica gel polygram SILG/UV 254 plates
or GLC on a Shimadzu GC-14A instrument. All yields refer
to the isolated products.
Acknowledgements
We are thankful to Shiraz University Research Council for
the partial support of this work. The technical assistance of
Mr Norooz Maleki is also acknowledged.
References
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