Application of SO3H silica gel to deprotection of silyl ethers

Article abstract of DOI:10.3987/COM-12-12577

A newly developed SO₃H silica gel cleaved the O-Si bonds in various aryl and alkyl silyl ethers to give the corresponding phenols and alcohols in good to excellent yield. The crude filtrates contained no silyl residues. The solid phase 29Si NMR analyses of the SO₃H silica gel strongly suggested that the silyl residues were captured by silanol groups on the surface of the silica gel. The SO₃H silica gel could be recycled at least ten times without any loss of activity. The disappearance of silyl residues in the crude filtrate was observed in even the 10th repetition. Our method provides an easily handled desilylation method that requires no further purification. Our method was also applicable to a selective desilylation reaction of a derivative 5 with different siloxy groups or desilylation of an alkaloid derivative 7.

Full text of DOI:10.3987/COM-12-12577

HETEROCYCLES, Vol. 85, No. 11, 2012
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HETEROCYCLES, Vol. 85, No. 11, 2012, pp. 2685 - 2691. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 5th September, 2012, Accepted, 25th September, 2012, Published online, 26th September, 2012
DOI: 10.3987/COM-12-12577
APPLICATION OF SO3H SILICA GEL TO DEPROTECTION OF SILYL
ETHERS
Hideaki Fujii,1 Takaaki Yamada,1 Kohei Hayashida,1 Miki Kuwada,1 Atom
Hamasaki,2 Kazunori Nobuhara,3 Sumio Ozeki,2 and Hiroshi Nagase1,*
1School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo
108-8641, Japan; e-MAIL: nagaseh@pharm.kitasato-u.ac.jp
2Department of Chemistry, Faculty of Science, Shinshu University, 3-1-1, Asahi,
Matsumoto, Nagano, 390-8621, Japan
3FUJI SILYSIA CHEMICAL LTD., 1846, 2-Chome, Kozoji-Cho, Kasugai-Shi,
Aichi, 487-0013, Japan
Abstract – A newly developed SO3H silica gel cleaved the O-Si bonds in various
aryl and alkyl silyl ethers to give the corresponding phenols and alcohols in good to
excellent yield. The crude filtrates contained no silyl residues. The solid phase 29Si
NMR analyses of the SO3H silica gel strongly suggested that the silyl residues were
captured by silanol groups on the surface of the silica gel. The SO3H silica gel could
be recycled at least ten times without any loss of activity. The disappearance of silyl
residues in the crude filtrate was observed in even the 10th repetition. Our method
provides an easily handled desilylation method that requires no further purification.
Our method was also applicable to a selective desilylation reaction of a derivative 5
with different siloxy groups or desilylation of an alkaloid derivative 7.
For several decades, solid-supported reagents have been widely used in organic synthesis.1 The
solid-supported reagents are expected to reduce waste products and to provide efficient and
environmentally benign processes. Indeed, solid catalysts can not only be easily separated from the reaction
products by simple filtration, but are also recyclable. We recently developed a silica gel whose surface was
modified by alkylsulfonic acid groups (SO3H silica gel)2 for the purpose of scavenging amines or purifying
acidic materials. Some applications of aryl sulfonic acid immobilized on silica gel have been reported:
cleavage of Bn, i-Pr, t-Bu, allyl, or MOM groups3 in aromatic ethers; an efficient preparation of o-quinone
methides for hetero Diels-Alder reaction;4 and for scavenging isocyanides.5 Reactions in the presence of

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7
silica sulfuric acid6 or silica gel supported NaHSO4 has also been reported. However, to the best of our
knowledge, there has been no application in organic synthesis of a SO3H silica gel on which alkylsulfonic
acid groups are immobilized. Herein, we report the first application of a SO3H silica gel to deprotection of
aryl or alkyl silyl ethers.
We attempted the cleavage of various aryl TBDMS ethers 1 (Table 1).8,9 The electron rich aryl silyl ether
was cleaved under milder reaction conditions (entry 3), whereas the reaction of the electron deficient aryl
silyl ether progressed more slowly (entry 1). The deprotections of all the tested TBDMS ethers 1 were
completed at 50 ºC or lower reaction temperature within 60 min to provide the corresponding phenolic
derivatives 2 in excellent yields except for 1b (entry 2). The sublimation property of phenol 2b may account
for the low isolated yield. Under the reaction conditions, benzoate was tolerate (entry 1), but aryl acetate
was labile (entry 8). This procedure was applicable to a large scale reaction (entry 4). It is noteworthy that
no signals stemming from silyl residues were observed in the 1H NMR analyses of the crude products. This
result indicates that this procedure can achieve the desilylation process without need for additional
purification.
Table 1. Desilylation of aryl TBDMS ethers 1
Temp Time Conversiona Yieldb
Temp Time Conversiona Yieldb
Entry
1
Compound
Entry
5
Compound
(ºC) (min)
(%)
(%)
(ºC) (min)
(%)
(%)
50
50
60
30
99
82
50
50
30
30
99
96
2
3
99
47
6
7
98
99
98
93
25
25
10
30
quant. quant.
50
50
30
30
OR'
4c
quant.
96
8
quant.
95
OR
1g: R=TBDMS, R'=Ac
2g: R=R'=H
a Conversion (%) was determined by the integral ratio of the 1H NMR of the crude product.
b Isolated yield.
c In this run, compound 1c (2.38g, 10 mmol) was used.

HETEROCYCLES, Vol. 85, No. 11, 2012
2687
Table 2. Desilylation of alkyl TBDMS ethers 3
Entry Compound Conversiona (%) Yieldb (%) Entry Compound Conversiona (%) Yieldb (%)
1
quant.
73c
4
97
88
2
quant.
72c
5
quant.
quant.
d
3
96
-
6
99
97
a Conversion (%) was determined by the integral ratio of the 1H NMR of the crude product.
b Isolated yield.
c The 1H NMR spectra of the crude product indicated only the alcohol 4.
d The ratio of alcohol 4c/styrene derivative was 1/8.
Table 3. Desilylation of p-methoxyphenyl silyl ethers 1
Temp Time Conversiona Yieldb
Temp Time Conversiona Yieldb
Entry
1
Compound
Entry Compound
3
(ºC) (min)
(%)
(%)
(ºC) (min)
(%)
(%)
50
30
87
NDc
50 120
42
NDc
2
50
120
quant.
79
4
100 120
quant.
91
a Conversion (%) was determined by the integral ratio of the 1H NMR of the crude product.
b Isolated yield.
c not determined. The isolated yield was not determined because the reaction was not complete.
We next applied the procedure to the deprotection of alkyl TBDMS ethers 3 (Table 2). All the tested alkyl
TBDMS ethers 3 were smoothly desilylated at 25 ºC to give the corresponding alcohols in good to excellent
yield except for 3c (entry 3), regardless of the structural feature; primary, secondary, or tertiary ethers were
all highly reactive. As we expected, the O-Si bonds of alkyl silyl ethers 3 were more easily cleaved and the
desilylation of alkyl silyl ethers 3 was completed under milder reaction conditions compared to aryl silyl
ethers 1.10 The reaction of silyl ether 3c provided a styrene derivative as the main product due to the

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HETEROCYCLES, Vol. 85, No. 11, 2012
MeO
MeO
SO3H silica gel
25 °C, 30 min
OTBDMS
OH
1c
2c
recycle, conversion, yield
1st
5th
10th
quant. quant.
quant.
99%
96%
97%
Scheme 1. Recycling of the SO3H silica gel for the desilylation of 1c
(a)
(b)
Figure 1. Solid phase 29Si NMR spectra (500 MHz). (a) Unused SO3H silica gel, (b) SO3H silica gel used
ten-times for the desilylation reaction. The signals at 18 ppm, -65 ppm, -100 ppm, and -111 ppm were
assigned to Si(O-Si)C3 (M1), Si(O-Si)2(OH)C (T2), Si(O-Si)3(OH) (Q3), and Si(O-Si)4 (Q4), respectively.
occurrence of an elimination reaction via the stable tertiary benzylic cation (entry 3). In the case of alkyl
TBDMS ethers, no silyl residues were also observed in the crude product. Although Das et al. reported the
deprotection of alkyl TBDMS ethers using silica gel supported NaHSO4, there was no description about the
silyl residues in the crude product.7k,11 Other aryl silyl ethers with silyl groups bulkier than TBDMS group
were applied to this procedure (Table 3). The TIPS or t-butyldiphenylsilyl (TBDPS) ethers are reported to
be 35- or 250-fold more stable toward acid than the TBDMS ethers.10 These bulky and stable silyl ethers
required higher reaction temperatures and/or longer reaction times for cleavage of their O-Si bonds as
compared to TBDMS ethers (entries 2 and 4). In contrast to the case of TBDMS ethers in which no silyl
residues were observed in the crude product, TIPS or TBDPS ethers provided crude product mixtures that
included TIPS or TBDPS residues. However, the use of far longer reaction times and/or higher reaction
temperatures decreased the amount of silyl residues in the crude products and, ultimately, almost no silyl
residues were detected.12
After removing the eluent under reduced pressure, the used SO3H could cleave the O-Si bond. The SO3H
silica gel was a reagent that was at least ten times recyclable without any loss of activity (Scheme 1). It is

HETEROCYCLES, Vol. 85, No. 11, 2012
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Scheme 2. Selective desilylation of compound 5
OH
OH
N
N
SO3H silica gel
50 °C, 2 h
conversion: quant.
yield: 95%
OH
OH
O
O
OTBDMS
OH
7
8
Scheme 3. Desilylation of compound 7
worthnoting that no silyl residues were detected in the crude product, even after the 10th run.13 We carried
29
out a solid phase Si NMR analysis of the SO3H silica gel, which had been used ten times for the
desilylation process (Figure 1b). In comparison with 29Si NMR spectrum of unused SO3H silica gel (Figure
1a), a signal was apparent at 18 ppm, which was assigned to Si(O-Si)C3 (M1), i.e. the trialkylsilyl group
bound to a silanol, in the 29Si NMR spectrum of the ten times used SO3H silica gel. Moreover, the relative
intensities of the signals at -65 and -100 ppm, which were assigned, respectively, to the silyl group in the
side chain14 and the silanol group on the surface of the silica gel, decreased compared to the intensity of the
signal at -111 ppm, which was thought to be unchanged because the signal arose from the structure of the
silica gel itself. These observations strongly suggested that the silyl residues provided by desilylation were
captured by silanol groups on the surface of the silica gel. The TBDMS group could smoothly react with the
silanol groups under these desilylation conditions. On the other hand, the bulkiness of the TIPS or TBDPS
groups would retard the reaction of the silyl groups with the silanol groups. As a result, the disappearance of
these bulky residues would require a longer reaction time and/or higher reaction temperature.
This procedure was applicable to a selective desilylation; compound 5 with different siloxy groups was
selectively converted into TBDPS ether 6 (Scheme 2). The O-Si bond of -naltrexol-3O-TBDMS ether (7)
was also cleaved to give -naltrexol (8) (Scheme 3).15
In conclusion, we found that the newly developed SO3H silica gel cleaved the O-Si bonds in various aryl
and alkyl silyl ethers to give the corresponding phenols and alcohols in good to excellent yields. These
methods provide the desilylation procedures without purification because the crude products contained no
silyl residues. The solid phase 29Si NMR analyses of the SO3H silica gel strongly suggested that the silyl
residues were captured by the silanol groups on the surface of the silica gel. The SO3H silica gel could be
recycled at least ten times without any loss of activity. The disappearance of silyl residues in the crude
product was observed in even the 10th repetition. The methods were also applicable to a selective
desilylation reaction or desilylation of an alkaloide derivative.

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8. General procedure: The mixture of SO3H silica gel (2 g) and the heptane solution9 of the silyl ether
(0.4 M, 1 mL) was shaken for one min and left to stand at an appropriate temperature. The silica gel
appeared to be powdered because only a small amount of solvent was used. After an appropriate
reaction time, the substrates were eluted by methanol and SO3H silica gel was removed by filtration.
9. Various solvents were applicable. See the supporting information in detail.
10. P. G. M. Wuts and T. W. Greene, 'Greene's Protective Groups in Organic Synthesis,' 4th ed. John Wiley
& Sons, New Jersey, 2007, p. 164.
11. According to reference 7k, the silica gel supported NaHSO4 could not cleave the bond O-Si bond of
the phenyl TBDMS ether.
12. The 1H NMR spectra of the crude products in the desilylation of 1i under various reaction conditions
(50 ºC, 120 min, higher reaction temperatures, and longer reaction times) are shown in the supporting
information.
13. The SO3H silica gel has silanol groups at the density of 1.8–2.3 mmol/g. Therefore, theoretically at
least 1.8–2.3 mmol of silyl residue was capable to be captured when the 1 g of the SO3H silica gel was
used.
14. The SO3H silica gel has side chains on which the SO3H groups are attached. The side chains are bound
to the silica gel through silica gel-O-C or (silica gel-O)2-Si-C bonds.
15. In this reaction, some amount of silyl residue remained in the crude product. Since compound 7 has a
basic nitrogen, SO3H groups immobilized on the silica gel might be partly neutralized to retard the
capture of silyl residues by silanols.