D. González-Calderón et al. / Tetrahedron Letters 54 (2013) 5130–5132
5131
Table 2
During one of our current research programs, we observed that the
bis-TBDMS ether 1a was cleaved within minutes upon microwave
heating in methanol containing CuSO4Á5H2O.
Chemoselectivity deprotection of TBDMS alkyl ethers in the presence of TIPS and
TBDPS phenyl ethers
OR
OR
This observation was not too surprising given that other cop-
per(II) salts such as CuBr2 in MeCN9 and CuCl2 in aqueous ace-
tone10 have been used for the de-protection of TBDMS ethers.
Interestingly, when we examined the deprotection of 1a in meth-
anol solutions of CuBr2 or CuCl2Á2H2O, compound 1 was formed
in considerably reduced yields of 50% and 55%, respectively. As a
consequence of the above results, we decided to investigate the
CuSO4Á5H2O cleavage of silyl ether 1a in more detail. Firstly, the
cleavage of 1a to 1 with this reagent was very inefficient in either
anhydrous acetonitrile or aqueous acetone (34% and 26% yields,
20 mol%
CuSO4 5H2O
OH
OTBDMS
MeOH
R = TIPS or TBDPS
Entry
Substrate
Producta
Yield (%)b
MWc
Dd
1
2
3
7a
8a
9a
7b
8b
9b
89
95
93
90
91
94
respectively). Secondly, the optimized conditions for the micro-
11
a
Confirmed by comparison with MS, 1H NMR, and 13C NMR with authentic
wave assisted
cleavage of 1a were heating at 100 °C for
sample.
15 min. in methanol containing 20 mol % CuSO4Á5H2O. With this
catalyst concentration, cleavage of 1a was slow at room tempera-
ture, but heating (conventional) at 50 °C resulted in acceptable
reaction rates, and a 12 h reaction period was adopted as the stan-
dard 12. The cleavage of a series of silyl ethers was then examined
under these optimized conditions (Table 1). The TBDMS ethers of
alkanols were cleaved cleanly in high yields, but the deprotection
of the TBDMS ethers of phenols was considerably less efficient.
The TIPS ethers of aliphatic alcohols also underwent cleavage
although the product yields were only modest. In contrast, TIPS
ethers of phenols, and the TBDPS ethers of both alcohol types re-
mained intact under both reaction conditions.
b
Yields refer to chromatographically pure isolated compounds.
100 °C, 15 min.
50 °C, 12 h.
c
d
Table 3
Cleavage of TBDMS alkyl ethers in the presence of TBDPS alkyl ethers by competition
experiments
20 mol%
CuSO4 5H2O
MeOH
Alkyl OH
Alkyl OTBDMS
+
Alkyl OTBDPS
+
Alkyl OTBDPS
The data in Table 1 clearly indicate that selective cleavage of
TBDMS alkyl ethers should be possible. Indeed, the results pre-
sented in Table 2 demonstrate that TBDMS alkyl ethers are cleanly
and efficiently removed in the presence of phenolic TIPS or TBDPS
ethers within the same molecule. In addition, an alkyl TBDMS pro-
tected species can be cleanly deprotected in the presence of an-
other alkanol protected as a TBDPS ether (Table 3).
A plausible mechanism for the Cu(II) catalyzed deprotection of
silyl ethers is shown in Scheme 1. Thus, complexation of the silyl
ether oxygen with Cu(II) weakens the silyl ether bond precipitating
the formation of a methoxy silyl ether, a proton, and a cupric alk-
Entry
Substrates
Productsa (Yield%)b
MWd
Dc
1
2
2a + 3c
3a + 2c
2 (95) + 3c (94)
3 (85) + 2c (98)
2 (91) + 3c (96)
3 (83) + 2c (98)
Confirmed by comparison with MS, 1H NMR, and 13C NMR with authentic
sample.
a
b
Yields refer to chromatographically pure isolated compounds.
50 °C, 12 h.
100 °C, 15 min.
c
d
R
O
SiR3
Table 1
Deprotection of silyl ethers using 20 mol % CuSO4Á5H2O in methanol
[cat]
H
R
O
H
Alkyl/Phenyl
SiR3= TBDMS, TIPS or TBDPS
Alkyl/Phenyl OH
OSiR3
Entry
Silyl ether
Alcohola
Yield (%)b,c
[cat]
O
MWd
De
[cat]
R
O
R
SiR3
1
2
3
4
5
6
7
8
1a
2a
2b
2c
3a
3b
3c
4a
4b
4c
5a
5b
5c
6a
6b
1
2
2
2
3
3
3
4
4
4
5
5
5
6
6
96
98
48
trace
80
15
NR
20
trace
NR
64
trace
NR
46
trace
94
98
51
NR
80
50
NR
20
trace
NR
58
trace
NR
40
Me
H
O
H
H
Me
[cat]
O
SiR3
H
O
Me
O
9
10
11
12
13
14
15
H
O
SiR3
silanol
Scheme 1. Proposed plausible mechanism for the cleavage of silyl ethers.
trace
a
Confirmed by comparison with MS, 1H NMR, and 13C NMR with authentic
sample.
anoate from which the alkanol is produced and the catalytic spe-
cies is regenerated. The catalyst also serves to convert the methyl
silyl ether into the corresponding silanol.
b
Yields refer to chromatographically pure isolated compounds.
In some cases no reaction occurred (NR) or product yields were very low and ca.
c
80–98% of starting material was recovered.
d
100 °C, 15 min.
50 °C, 12 h.
In conclusion, we report that catalytic CuSO4Á5H2O in methanol
e
solution, effects the efficient and selective deprotection of alkyl