LETTER
Facile Cleavage of Silyl Ethers
1261
OTBS (Table 1, entry 10). Increased amounts of the Solvent apparently had a strong effect on the cleavage
added FeCl3 to 6.6 × 10–2 equivalents remarkably short- reaction. It appeared that use of an alcoholic solvent was
ened the reaction time (Table 1, entry 11). Cleavage of important for the desired reaction to take place. The most
primary OTIPS in synthetically useful yields within rea- satisfactory results were obtained in MeOH. When using
sonable time required even larger amounts of FeCl3 EtOH as the solvent, the reaction became substantially
(Table 1, entries 13, 15).
slower, although the outcomes (yields) were more or less
the same. The desilylation process was further slowed in
MeCN and completely shut down in THF. Hwu2k and co-
workers postulated a single-electron-transfer mechanism
for their CAN-catalyzed removal of TBS groups. Most
results presented here appear to be compatible with that
mechanistic picture. However, the facile reaction cata-
lyzed by e.g., CrCl3·6H2O or SnCl2·2H2O was very diffi-
cult to fit into that mechanism, because single-electron
reduction of Cr(III) to Cr(II) required a powerful reduc-
tant and conversion of Sn(II) to Sn(I) was probably not
known.
It should be noted that the desilylation reaction did not re-
quire exclusion of moisture and no discernible difference
between FeCl3 and FeCl3·6H2O was observed in the
desilylation process.
The mechanism of the deprotection catalyzed by FeCl3
was not clear yet. However, the cleavage of the oxygen–
silyl bonds does not seem to be caused by low pH values,
because in all those runs with far less than stoichiometric
amounts of FeCl3 the reaction medium was essentially
neutral (pH 6–7). The solutions containing near stoichio-
metric amounts of FeCl3 (Table 1, entries 13 and 15) were
indeed acidic (pH 2). However, using an equally acidic
methanolic HCl solution (pH 2) to replace the FeCl3 solu-
tion did not lead to any desilyl product at all under the oth-
erwise identical conditions (Table 1, entry 15).
The large difference in the cleavage reaction rate listed in
Table 1 suggested the possibility of removing a labile silyl
protecting group in the presence of a more stable one,
which was often desired in the synthesis of complicated
molecules. We first examined a linear bifunctional sub-
strate TBSO(CH2)4OTES (Table 3, entry 1). Under the
conditions (1.8 × 10–3 equiv of FeCl3) that were quite ef-
fective to deprotect unhindered primary OTES within
minutes but apparently still too weak for cleaving OTBS
groups in similar substrates, the expected mono-depro-
tected product TBSO(CH2)4OH was isolated in 80% yield
after 15 minutes reaction. However, somewhat to our sur-
prise, the fully deprotected product diol HO(CH2)4OH
was also obtained in 15% yield (where the TBS group was
also removed!). When the OTES was replaced with an
OH, the TBS group could also be removed in a similar
yield (19%) within 15 minutes (Table 3, entry 2). Further
extending the reaction time to 3 hours led to 80% removal
of the TBS group (Table 3, entry 3). Note that in sub-
strates like Ph(CH2)2OTBS (Table 1, entry 10), where the
additional OTES or OH was absent, deprotection of the
TBS groups was much slower.
Table 2 Reaction of PhCH2CH2OTES to PhCH2CH2OH at Room
Temperature in MeOH Catalyzed by Different Inorganic Saltsa
Entry Catalyst (equiv)b
Time
20 h
Yield (%)
No reaction
100
1
2
3
4
5
6
7c
NiCl2·6H2O (3.0 × 10–3)
CuSO4 (4.4 × 10–3)
CoCl2 (5.4 × 10–3)
7 h
20 h
No reaction
100
CrCl3·6H2O (2.2 × 10–3)
SnCl2·2H2O (3.1 × 10–3)
FeCl2 (1.8 × 10–3)
10 min
10 min
1.5 h
5 min
90
98
FeCl3 (1.8 × 10–3)
100
a The pH value of the reaction medium was 6–7.
b With respect to the substrate.
c Data taken from Table 1 for comparison.
When the spacer between the OTBS and OTES was a
relatively rigid one (Table 3, entries 3, 4), which excluded
any possible intramolecular contact between the two pro-
tecting groups through folding-back of the flexible alkyl
chain, the TBS group was no longer so liable and the yield
of the mono-deprotected products was significantly raised
(Table 3, entries 4, 5). These data suggested that the pres-
ence of an OTES or OH group that was ‘accessible’ to the
OTBS might facilitate the cleavage of the TBS group,
although the mechanism was still to be revealed.
On the other hand, some other inorganic salts (Lewis
acids), such as CuSO4, CrCl3·6H2O, or SnCl2·2H2O, were
also able to cleave the TES group in Ph(CH2)2OTES
(Table 2). Exclusion of the air in the solvent (by bubbling
argon/evacuating with an aspirator) and running the reac-
tions under an argon atmosphere did not lead to any dis-
cernible difference in the reaction rate/outcome.
However, starting with FeCl2 instead of FeCl3 did result in
substantially slower cleavage (Table 2, entry 6 vs. 7). It is
well-known that Fe(II) is very liable to air oxidation.
Therefore, the observed first slow then normal desilyla-
tion reaction was likely because existence of a relatively
slow (due to rather low content of oxygen in the reaction
system after the degassing operation) conversion of Fe(II)
to Fe(III) at the initial stage. It is interesting to note that
not all salts (Lewis acids) tested were effective.
NiCl2·6H2O and CoCl2·2H2O, for instance, were com-
pletely inactive (Table 2, entries 1 and 3).
Finally, as one may easily deduce from the slow cleavage
reactions of the more stable (compared with TBS) TIPS
and ‘inert’ TBDPS groups, selective removal of TES
protecting group in the presence of a TIPS and/or TBDPS
group was also feasible (Table 3, entries 6–8). Even
selective removal of a primary TBS groups in the
presence of a TIPS or TBDPS group was also possible
(Table 3, entries 9–11).
Synlett 2006, No. 8, 1260–1262 © Thieme Stuttgart · New York
Yang, Yong-Qing
