A facile, selective KF/Al2O3 mediated method for the deprotection of aryl silyl ethers and preparation of aryl SEM ethers

Article abstract of DOI:10.1016/S0040-4039(00)02259-0

A selective, solvent dependent KF/Al₂O₃ mediated method for the cleavage of aryl silyl ethers and the preparation of SEM aryl ethers is reported.

Full text of DOI:10.1016/S0040-4039(00)02259-0

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1611–1613
A facile, selective KF/Al2O3 mediated method for
the deprotection of aryl silyl ethers and preparation of
aryl SEM ethers
Benjamin E. Blass,* Cheryl L. Harris and David E. Portlock
Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason Montgomery Road, Mason, OH 45040, USA
Received 5 October 2000; accepted 1 December 2000
Abstract—A selective, solvent dependent KF/Al2O3 mediated method for the cleavage of aryl silyl ethers and the preparation of
SEM aryl ethers is reported. © 2001 Elsevier Science Ltd. All rights reserved.
Over the past century, the science of organic chemistry
has made great strides forward in part due to the
development of effective protecting group strategies.
Organosilicon reagents have played an important role
in this area, due to their stability under a broad range
of reaction conditions. Although originally introduced
in the late 1950s as tools to facilitate gas chromatogra-
phy and mass spectrometry, the utility of organosilicon
reagents in organic synthesis was not recognized until
the early 1970s.1 Since that time, their use has under-
gone an explosive growth, and numerous methods for
the preparation and subsequent removal of organosilyl
ethers have been developed. The most common meth-
ods for the deprotection of silyl ethers include the use
of mild acids (e.g. TFA, formic acid) and fluoride
reagents (e.g. TBAF, HF/pyridine, KF/18-crown-6).2
Recently, we have examined the application of solid
supported reagents, in particular, potassium fluoride on
alumina (KF/Al2O3), and their potential utility in
deprotection of silyl ethers. We now wish to report that
neutral KF/Al2O3 efficiently, selectively, and cleanly
removes a variety of silyl protecting groups from phe-
nols. The process is solvent dependent, allowing for the
selective cleavage of TMS, TBDMS, or TDBPS groups.
It is also possible to differentiate between electron rich
and electron poor phenolic ethers, as this reaction
shows strong solvent effects. In addition, carbon/silicon
bonds are not affected, as the SEM protecting group is
stable to this reagent under a variety of conditions. For
example, we have found that neutral KF/Al2O3 can
replace tertiary amine bases in the preparation of phe-
nolic SEM ethers. This new method is simpler than
most of those available, as there is no aqueous work-up
and the products are isolated by filtration and removal
of the solvent.
Potassium fluoride on alumina (KF/Al2O3) was initially
reported in 1981 by Yamawaki as a base for functional-
Table 1. Solvent effects of KF/Al2O3 mediated deprotection of silyl ethers10
Entry
R
DME/time
DCE/time
1,4-Dioxane/time
Temp. (°C)
1
2
3
4
TMS
95%/4 h
92%/4 h
95%/4 h
0%/16 h
95%/4 ha
0%/16 h
0%/16 h
0%/16 h
95%/4 h
94%/16 h
0%/16 h
0%/16 h
25
25
25
75
TBDMS
TBDPS
SEM
a After completion, the reaction was diluted with an equivalent volume of DME to dissolve the product.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02259-0

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
1612
B. E. Blass et al. / Tetrahedron Letters 42 (2001) 1611–1613
Table 2. Representative examples of KF/Al2O3 mediated deprotection of silyl ethers
Entry
R
Protecting group
Solvent
Time (h)
Temp. (°C)
Conversion (%) Yield (%)
1
2
3
4
5
6
7
8
2-Br-C6H4
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
TBDMS
DME
DME
DME
DME
4
4
4
4
4
16
16
16
16
16
16
16
25
25
25
25
25
25
25
25
25
25
25
25
100
100
100
100
100
100
100
100
0
92
4-NO2-C6H4
4-CO2Bn-C6H4
4-Ph-C6H4
4-TBDMSO(CH2)2C6H4
2-Br-C6H4
4-NO2-C6H4
4-CO2Bn-C6H4
4-Ph-C6H4
4-TBDMSO(CH2)2C6H4
n-C8H17
93a
92
95
87
DME
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
DME
92
93a
95
9
N/A
N/A
N/A
N/A
10
11
12
0
0
0
n-C8H17
1,4-Dioxane
a After completion, 24 equivalents of acetic acid was added assist in product recovery.
ization of amides.3 Morgan has reported the KF/Al2O3
mediated alkylation of 2,4-dinitrophenylhydrazones,4
and Tius recently demonstrated that KF/Al2O3 is useful
for the preparation of a-heterosubstituted Weinreb
amides.5 We have reported our findings that this
reagent can facilitate the functionalization of 2-
oxazolidinones6 and also allows selective alkylation of
benzodiazepin-2,5-diones.7 In an effort to extend the
utility of this versatile reagent, we have examined its
ability to cleave silyl ethers under a variety of condi-
tions. Sawyer has reported that both acidic and basic
KF/Al2O3 can cleave phenolic TBDMS ethers in aceto-
nitrile, and that the reaction rates were generally higher
for basic alumina. In addition, ultrasound was found to
increase the rate of cleavage of the silyl ether.8 We have
since found that neutral KF/Al2O3 can effectively
remove a wide range of silyl ethers in a solvent depen-
dent manner, without the aid of ultrasound. The reac-
tion can also be fine tuned to allow for differentiation
between various silyl ethers, as the rates of cleavage of
TMS, TBDMS, TBDPS, and SEM9 phenolic ethers
vary greatly depending on the choice of solvent. Thus,
trimethylsilyl-4-bromophenol (Table 1, entry 1) was
readily deprotected with neutral KF/Al2O3 in DME,
DCE or 1,4-dioxane after only 4 hours at 25°C. t-
Butyldimethylsilyl-4-bromophenol (Table 1, entry 2),
however, was found to be stable after 16 hours in DCE
in the presence of neutral KF/Al2O3. Switching solvents
to DME facilitated cleavage of the TBDMS group,
which was accomplished after only 4 hours at 25°C.
The solvent dependence of this reaction is further
demonstrated by the decrease in the reaction rate when
the solvent is changed to 1,4-dioxane. The conversion
of t-butyldimethylsilyl-4-bromophenol to the corre-
sponding phenol in 1,4-dioxane requires 16 hours. The
TBDPS analog is stable to these conditions. Removal
of the TBDPS group can, however, be accomplished in
4 hours in DME. Interestingly, the SEM protected
analog of 4-bromophenol is stable to all of the afore-
mentioned conditions, and no product was detected in
DCE, DME or 1,4-dioxane after 16 hours at 75°C.
Upon examination of a broader array of silyl protected
ethers (Table 2), we discovered some additional aspects
of this reaction. First, alkyl silyl ethers are not cleaved
under any of the conditions examined, as indicated by
the recovery of starting materials in examples 11 and
12. Differentiation between alkyl and aryl silyl ethers is
clearly displayed by the selective deprotection of entry
5, which produced the monosilylated phenol, rather
than the diol.11 Second, while electron poor TBS phe-
nolic ethers are cleaved in 1,4-dioxane after 16 hours
(Table 2, entries 6–8), electron rich TBS phenolic ethers
are stable, as indicated by the recovery of starting
materials in entries 9 and 10.
The unusually strong solvent dependence of this reac-
tion and the stability of the SEM protected phenols to
these conditions suggested that KF/Al2O3 might also be
suitable for the preparation of SEM ethers. This would
provide a simplified method of preparation of SEM
ethers, as removal of the base (in this case, KF/Al2O3)
would not require an aqueous work-up. Treatment of a
series of phenols with 1.0 equivalents of SEM-Cl in the
presence of KF/Al2O3 in DME produced the desired
SEM ether in high yield, as indicated in Table 3. This
procedure is effective for both electron rich and poor
phenols, but as indicated by entry 7, alkyl SEM ethers
can not be prepared using this method.
Table 3. Representative examples of KF/Al2O3 mediated
SEM ether preparation12
Entry
R
Yield (%)
1
2
3
4
5
6
7
4-Br-C6H4
2-Br-C6H4
94
92
96
89
88
95
0
2,4-Di-Br-C6H4
4-Ph-C6H4
4-NO2-C6H4
4-CO2Bn-C6H4
n-C8H17

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
B. E. Blass et al. / Tetrahedron Letters 42 (2001) 1611–1613
1613
The solvent effects observed in these reactions could be
explained by a solvent dependence on the basicity of
the KF/Al2O3. In less polar, non-chelating solvents,
such as DCE, ion pairing of the KF is high. This limits
the ability of KF/Al2O3 in DCE to cleave silyl ethers,
and as a result, only the weakest silyl protecting group,
TMS, is removed. As the polarity and chelating ability
of the solvent is increased, the ion pairing of the KF is
decreased via chelation of the potassium, thus allowing
more stable silyl protecting groups (e.g. TBS and
TBDPS) to be removed. The limitation of this are
clearly indicated by the stability of the SEM group,
which is stable to all of the conditions we examined.
3. Yamawaki, J.; Ando, T.; Hanafusa, T. Chem. Lett. 1981,
1143–1146.
4. Morgan, L. R.; Thangaraj, K. Synth. Commun. 1994, 24,
2063–2067.
5. Tius, M. A.; Busch-Pertersen, J. Synlett 1997, 531–532.
6. Blass, B. E.; Drowns, M.; Harris, C. L.; Liu, S.; Portlock,
D. E. Tetrahedron Lett. 1999, 40, 6545–6547.
7. Blass, B. E.; Burt, T. M.; Liu, S.; Portlock, D. E.; Swing,
E. M. Tetrahedron Lett. 2000, 41, 13, 2063–2066.
8. Sawyer, S. J.; Schmittling, E. A. Tetrahedron Lett. 1991,
32, 7207–7210.
9. TMS=trimethylsilyl, TBDMS=tert-butyldimethyl silyl,
TBDPS=tert-butyldiphenyl silyl, SEM=2-(trimethylsi-
lyl)ethoxy methyl.
In summary, we have developed a new, selective
method for the cleavage of aryl silyl ethers in the
presence of alkyl silyl ethers. Furthermore, the method
can be used to selectively remove less bulky aryl silyl
ethers in the presence of their more sterically hindered
counterparts. Finally, the method can be used to pre-
pare aryl SEM ethers. The products are obtained in
excellent yields, and the selectivity of the reaction can
be tuned by the appropriate choice of solvents.
10. Typical experimental procedure: t-Butyldimethylsilyl-4-
bromophenol (32.1 mg, 27.3 mL, 0.11 mmol) is dissolved
in 2.0 ml of DME and 172 mg of KF/Al2O3 (40% wt.
KF) is added. The reaction is stirred at room temperature
for 4 hours, filtered and stripped to an oily solid. Chro-
matography with 3/1 hexane/ethyl acetate provided 17.5
mg of 4-bromophenol.
11. Removal of the aryl silyl ether was confirmed by analysis
of mass spectral fragmentation patterns.
12. Typical experimental procedure: 4-Bromophenol (100
mg, 0.56 mmol) and 890 mg of KF/Al2O3 (40% wt. KF)
are dissolved/suspended in 5.0 ml of DME and 102 mL of
SEM-Cl (96.2 mg, 0.56 mmol) is added. The reaction is
then stirred 2 hours, filtered and stripped to yield 165 mg
(94%) of the desired product. No further purification was
required.
References
1. Lalonde, M.; Chan, T. H. Synthesis 1985, 817–845.
2. Greene, T. W.; Wuts, P. G. Protective Groups in Organic
Synthesis; John Wiley & Sons: New York, 1991; pp.
68–87.
.
.