Transprotection of silyl ethers of nucleosides in FeCl3 based ionic liquids

Article abstract of DOI:10.1081/NCN-200060305

Ionic liquid mediated deprotection of tert-butyldimethyl silyl (TBDMS) ethers derived from various primary and secondary alcohols have been studied and the reaction conditions optimized. Deprotection of the silyl ethers in FeCl₃ based ionic liquids in presence of acetic anhydride yielded the acetate esters of the corresponding alcohols in good yields. The transprotection methodology was extended to the silyl ethers of nucleosides to yield the corresponding acetylated products. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/NCN-200060305

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TRANSPROTECTION OF SILYL ETHERS OF NUCLEOSIDES
IN FeCl BASED IONIC LIQUIDS
3
a
a
a
b
Jitendra R. Harjani , Susheel J. Nara , Manikrao M. Salunkhe & Yogesh S. Sanghvi
a
Department of Chemistry , The Institute of Science , Mumbai, India
b
Rasayan Inc. , Encinitas, California, USA
Published online: 15 Nov 2011.
To cite this article: Jitendra R. Harjani , Susheel J. Nara , Manikrao M. Salunkhe & Yogesh S. Sanghvi (2005)
TRANSPROTECTION OF SILYL ETHERS OF NUCLEOSIDES IN FeCl BASED IONIC LIQUIDS, Nucleosides, Nucleotides and Nucleic
3
Acids, 24:5-7, 819-822, DOI: 10.1081/NCN-200060305
To link to this article: http://dx.doi.org/10.1081/NCN-200060305
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (5–7):819–822, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200060305
TRANSPROTECTION OF SILYL ETHERS OF NUCLEOSIDES IN FeCl3
BASED IONIC LIQUIDS
5
Jitendra R. Harjani, Susheel J. Nara, and Manikrao M. Salunkhe
Department
of Chemistry, The Institute of Science, Mumbai, India
5
Yogesh S. Sanghvi
Rasayan Inc., Encinitas, California, USA
5
Ionic liquid mediated deprotection of tert-butyldimethyl silyl (TBDMS) ethers derived from various
primary and secondary alcohols have been studied and the reaction conditions optimized. Deprotection of
the silyl ethers in FeCl based ionic liquids in presence of acetic anhydride yielded the acetate esters of
3
the corresponding alcohols in good yields. The transprotection methodology was extended to the silyl
ethers of nucleosides to yield the corresponding acetylated products.
Keywords Protected Nucleosides, Ionic Liquid, Desilylation, Acylation
INTRODUCTION
Among the silyl protecting groups, the tert-butyldimethyl silyl (TBDMS) ethers
of the alcohols provide low-cost and synthetic advantages. Additionally, the
TBDMS ethers are stable to hydrogenolysis, Jones oxidation, mild chemical
reductions and THP ether cleavage. One of the key feature of TBDMS ethers is
their ability to be cleaved selectively in the presence of the other silyl protecting
[
1]
group(s). Survey of the literature indicated that the protocols used for the cleavage
[2–4]
of silyl ethers either employ Lewis acids or water in presence of acid or base.
The literature methodologies were of limited utility and interest to us, as our goal
was to develop a protocol that was non-hydrolytic. This is because most of the -OH
and -NH protecting groups employed routinely in nucleoside chemistry are
sensitive towards acid and base hydrolysis. FeCl is reported to act as an efficient
3
Lewis acid catalyst. With the growing interest in applications of the ionic
[
5–9]
liquids,
we considered it worthy to use 1-butyl-3-methylimidazolium chloride
[
bmim]ClFeCl , N = 0.35–0.60 ionic liquid for the desilylation of silyl ethers.
3
Address correspondence to Manikrao M. Salunkhe, Department of Chemistry, The Institute of Science, 15
Madam Cama Road, Mumbai 400 032, India.
819
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820
J. R. Harjani et al.
SCHEME 1 [bmim]ClFeCl
3
, N = 0.60 mediated desilylation of TBDMS ethers.
RESULTS AND DISCUSSION
The [bmim]Cl.xFeCl system is liquid when the apparent mole fraction of
3
[10]
FeCl , N in the ionic liquid is in the range N = 0.35–0.60. We conducted the
3
experiments using benzyloxy-tert-butyldimethylsilane as a model substrate. The
ionic liquids of different Lewis acidities were added in the stiochiometric amounts
to the reaction mixture (1 mol equiv. used for each reaction). The reactions were
stopped after 30 min, and were assayed on GC to quantify the extent of conversion
obtained at different Lewis acidities. The extent of conversion was dependent on
the Lewis acidity of the ionic liquid. Thus, the ionic liquid with N = 0.35 provided
1
2% conversion, while the reaction with N = 0.50 showed 22% conversion within
3
0 min. Extending the reaction time to 24 h improved the conversion to 45%
(
N = 0.50). The ionic liquid [bmim]FeCl , N = 0.60 proved to be superior to all
3
other ionic liquids with 100% conversion in 30 min. Therefore, we chose
[
bmim]ClFeCl , N = 0.60 ionic liquid in our deprotection studies.
3
Next, we studied the effects of using a molar equivalence of ionic liquid with
N = 0.60 in the reaction mixtures. We quantified the extent of conversion in each
case by arbitrarily fixing the time at 30 min. The results indicated that the
conversion was directly dependent on the molar stoichiometry of the ionic liquid in
the reaction. An increase in the molar stoichiometry from 0.25 equivalent to 0.50
equivalent increased the conversion from 18 to 43%. A further increase in the molar
equivalence to 0.75 resulted in a 72% conversion. The conversion was found to be
quantitative with 1 mol equivalent of ionic liquid. The reaction time was further
optimized via desilylation of benzyloxy-tert-butyldimethyl-silane using 1 mol
equivalent of ionic liquid. The progress of the reaction was monitored at 5, 10,
1
5, and 20 min. A 62% conversion was observed after 5 min, which increased to 89%
after 10 min. The conversions reached a maximum of 100% within 15 min. These
3
SCHEME 2 [bmim]ClFeCl , N = 0.60 mediated transprotection of TBDMS ethers.

J. R. Harjani et al.
821
TABLE 1 Transprotection of Silylated Nucleosides in [bmim]ClFeCl
Anhydride
3
, N = 0.60 in Presence of Acetic
a
Entry
Silylated nucleoside
Product
Yields (%)b
1
76
88
2
3
72
62
4c
a
2
3 2
mol equiv. of [bmim]ClFeCl , N = 0.60/2.2 mol equiv. of Ac O/30 min/rt.
b
Isolated yields.
c
Reaction carried out for 3 h.
being the optimal conditions for desilylation, the protocol was utilized for silyl
ethers derived from primary, secondary and cyclic secondary alcohols to evaluate
the success of our methodology. Gratifyingly, excellent desilylation of a variety of
molecules was accomplished under the optimized conditions (Scheme 1).*
Furthermore, we studied the desilylation reaction in the presence of acetic
anhydride. Interestingly, we observed a rapid transprotection of silylated substrates
which furnished acetylated products in good yields (Scheme 2).* Extension of this
*Preparation of 1-butyl-3-methylimidazolium chloride, [bmim]Cl: The mixture of 100 mmol 1-methylimidazole
and 400 mmol 1-chlorobutane in 12 mL dried toluene was refluxed under nitrogen atmosphere for 24 h to obtain a
viscous liquid forming the lower layer. The reaction mixture was cooled to 0°C overnight to yield the solid
quaternary salt (1-butyl-3-methylimidazolium chloride). The excess unreacted toluene and 1-chlorobutane was
decanted and the salt washed with diethyl ether (3 Â 10 mL). The salt was further purified by recrystallization from
3
acetonitrile/ethyl acetate to yield the pure product. Melting point: 66–68°C. Preparation of [bmim]Cl.xFeCl :
3
Appropriate quantities of 1-butyl-3-methylimidazolium chloride and FeCl (depending on the Lewis acidity of the
ionic liquid required) were mixed in a round bottom flask and stirred under cold conditions (0–10°C) to avoid
local overheating. Upon stirring (30 min), the two solids fused together, resulting in the formation of a clear ionic
liquid, [bmim]ClFeCl
ionic liquid, 2 mmol of silyl ether was added and the mixture was stirred at room temperature under inert
atmosphere. The reaction mixture was quenched by adding aqueous saturated NaHCO and extracted with diethyl
ether (3 Â 5 mL). The combined organic layer was dried over anhydrous Na SO and evaporated under reduced
pressure. The products were purified by silica gel chromatography to furnish the alcohol. General procedure for
transprotection: To 5 mmol of [bmim]Cl.FeCl , N = 0.60 ionic liquid, 5 mmol of silyl ether, and 5.5 mmol of acetic
3 3
, N = 0.35–0.60. General procedure for desilylation: To 2 mmol of [bmim]ClFeCl , N = 0.60
3
2
4
3
anhydride were added and the mixture was stirred at room temperature under inert atmosphere. The reaction
mixture was worked up as described above to furnish the acylated product.

822
J. R. Harjani et al.
protocol to TBDMS protected 2’-deoxyribonucleosides furnished acetylated
products in 62–88% yields (Table 1).* The protocol used 2 mol equivalent of
[
bmim]Cl.FeCl , N = 0.60 and 2.2 mol equivalent of Ac O for the disilyl derivatives
3
2
to yield the nucleoside diacetates. The optimal time for the reaction was 1 h;
however, the monosilyl derivative took a longer time (entry 4, Table 1).
CONCLUSION
The [bmim]ClFeCl , N = 0.60 ionic liquid served as an efficient solvent-catalyst
3
system for achieving the desilylation of alcohols. The desilylation protocol in
[
bmim]Cl.xFeCl has been optimized for the Lewis acidity and reaction time. The
3
FeCl based ionic liquid was efficient in promoting the desilylation reaction of silyl
3
ethers of nucleosides in presence of acetic anhydride, generating the corresponding
acetate esters.
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