A mild and efficient desilylation of O-tert-butyldimethylsilyl ethers mediated by chlorotrimethylsilane and potassium fluoride dihydrate in acetonitrile

Article abstract of DOI:10.1055/s-2006-932474

Desilylation of O-tert-butyldimethylsilyl ethers was achieved by a reagent system consisting of chlorotrimethylsilane and potassium fluoride dihydrate in acetonitrile. This alternative desilylation procedure is chemoselective, generally effective and operationally simple, and should find practical applications in organic synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-932474

LETTER
1165
A Mild and Efficient Desilylation of O-tert-Butyldimethylsilyl Ethers Mediated
by Chlorotrimethylsilane and Potassium Fluoride Dihydrate in Acetonitrile
Desilylation of
O
-
t
u
ert-butyldimethyls
P
ilyl
E
the
r
withe 2
T
MSCl/K
n
F
·2H O in M
g
eC
N
, Wei-Dong Z. Li*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912539; E-mail: liwd@lzu.edu.cn; E-mail: isoc@lzu.edu.cn
Received 5 October 2005
properties of these reagent systems have constrained its
Abstract: Desilylation of O-tert-butyldimethylsilyl ethers was
achieved by a reagent system consisting of chlorotrimethylsilane
and potassium fluoride dihydrate in acetonitrile. This alternative
desilylation procedure is chemoselective, generally effective and
utilization in many occasions. We assumed that KF·2H2O
might provide a fluoride source for the generation of HF
in situ in the presence of TMSCl as a mild Lewis acidic
operationally simple, and should find practical applications in mediator in a polar solvent system, i.e. MeCN, based on a
organic synthesis.
hypothetical equilibrium depicted in Equation 1.
Key words: desilylation, potassium fluoride, chlorotrimethyl-
silane, O-tert-butyldimethylsilyl ether
In a recent synthetic program in our Laboratory, we de-
vised a reagent system consisting of TMSCl and KF·2H2O
in MeCN for the desilylation of secondary O-TBS ether
derivative 1 to the corresponding alcohol 2 (Equation 2),
Since its introduction by Corey and Venkateswarlu in
1972,1 the tert-butyldimethylsilyl (TBDMS or TBS) group
has emerged as one of the most commonly used protecting
groups2 for the hydroxyl functionality in synthetic organic
chemistry due to its easy introduction and general stability
to a wide variety of reaction conditions involving basic,
mildly acidic, or various organometallic reagents. Al-
though numerous reagents and protocols2 have been de-
veloped for the selective cleavage of O-TBS ethers, it is
still desirable to search for an effective method under mild
reaction conditions, while performing the desired desilyl-
ation in a chemoselective manner by using an inexpensive
and readily available reagent or reagent system. As a re-
sult, a number of novel reagents or reagent systems have
appeared in recent literatures3 for selective desilylation of
O-TBS ethers. Nonetheless, most of these methods in-
volved somewhat acidic, basic, reductive or oxidative
conditions that limited their practical applications. We re-
port herein a simple and effective method for the desilyla-
tion of O-TBS ethers to their parent hydroxy compounds
mediated by a reagent system consisting of chlorotri-
methylsilane (TMSCl) and potassium fluoride dihydrate
(KF·2H2O) in acetonitrile.
as a result of the same reaction under conventional condi-
tions (48% HF in MeCN at r.t.) required more than 48
hours to complete and tedious work up procedure for the
removal of large excess HF. Thus, a slurry mixture of O-
TBS ether 1 and finely powdered KF·2H2O (ca. 200 mesh,
1.0 equiv) in anhydrous MeCN was vigorously stirred at
room temperature (22 °C) for 15 minutes, there is no de-
tectable (by TLC) desilylated product 2 formed. Upon
treatment of the above reaction mixture with freshly dis-
tilled TMSCl (1.0 equiv), the reaction mixture became
slightly cloudy and TLC showed the completion of the
desilylation in five minutes. The desired desilylated
alcohol 2 was obtained in 85% isolated yield after flash
column chromatography on silica gel.
TMSCl, KF⋅2H2O
MeCN, r.t., 5 min
OTBS
OH
n-C11H23
OTs
n-C11H23
OTs
85%
1
2
Equation 2
To evaluate the generality of this reagent system for de-
silylation, we next examined the solvent effect by em-
ploying secondary O-TBS ether 3 derived from (–)-
menthol as a substrate (Table 1).
MeCN
KF⋅2H2O
+
+
+ HF⋅H2O
TMS-OH
TMS-Cl
KCl
It is obvious that MeCN and MeOH are the most suitable
solvents leading to a very rapid desilylation. Polar aprotic
solvents (DMF, NMP and DMSO) are generally good al-
though the reactions are much slower. Ethereal solvents
(THF and Et2O) resulted in slower and incomplete reac-
tion. There is no observable reaction occurred in hydro-
carbon solvents, such as benzene, while halogenated
solvents, i.e. CH2Cl2 and CHCl3, are much less effective
reaction medium.
Equation 1
Potassium fluoride, a least expensive and readily available
fluoride source, has been widely used in an anhydrous
form to cleave the phenolic O-TBS ethers under various
conditions,4 as well as a dihydrated form for the in situ
generation of n-tetrabutylammonium fluoride (TBAF) re-
sponsible for desilylation.5 However, the strong basic
To further investigate the roles of KF, TMSCl and H2O,
we set out to perform the desilylation of O-TBS in MeCN
by using KF in the presence or absence of either TMSCl
SYNLETT 2006, No. 8, pp 1165–1168
Advanced online publication: 10.03.2006
DOI: 10.1055/s-2006-932474; Art ID: W30305ST
© Georg Thieme Verlag Stuttgart · New York
1
5.
0
5.
2
0
0
6

1166
Y. Peng, W.-D. Z. Li
LETTER
Table 1 Solvent Effects of Desilylation by (TMSCl + KF·2H2O)a
Table 2 Role of KF, TMSCl and H2O in Desilylationa
OH
OTBS
OH
OTBS
TMSCl, KF⋅2H2O
reagent system
CH3CN, r.t.
solvent, r.t.
3
3
Entry
1
Reagent system and ratio Reaction time Yield (%)b
Entry
Solvent
Reaction time
5 min
10 h
Yield (%)b
KF·2H2O:TMSCl
1:0
2 h
0c
1
2
MeCN
CH2Cl2
C6H6
95
50c
0
2
3
4
KF:TMSCl
1:1
2 h
0c
3
10 h
4
THF
5 h
85c
50c
80c
45c
90
90
95
KF·2H2O:TMSCl
1:1
5 min
4 h
95
5
Et2O
5 h
KF·2H2O:TMSCl
1:0.1
90
6
DMSO
CHCl3
DMF
10 h
a (–)-Menthol O-TBS ether 3 was used as substrate, anhyd KF were
used as finely powders, and the reaction was carried out in freshly
distilled anhyd MeCN in 2.5 mmol scale.
b Average isolated yields.
7
10 h
8
2 h
9
NMP
48 h
c No detectable reaction occurred, starting O-TBS ether was
recovered.
10
MeOH
5 min
a Reactions were performed as described for the desilylation of 1 (see
experimental procedure) in a 2.5 mmol scale.
b Average isolated yields.
pyranyl, and bulkier O-trialkylsilyl group (such as tert-
butyldiphenylsilyl, TBDPS), as well as the acid-labile
functional group (b-lactone in compound 12), remain
intact under this mild conditions as demonstrated in the
desilylation of compounds 1, 11–13, and 15.
c Incomplete reactions, starting O-TBS ethers were partially
recovered.
or water (Table 2). It is apparent that the presence of
hydrated H2O is essential for the complete desilylation
reaction (entry 1 vs. 2). Despite a relatively slower reac-
tion rate, a catalytic amount of TMSCl can be employed
to achieve a nearly complete desilylation (entry 3 vs. 4). It
was concluded from the above facts that H2O plays a crit-
ical role6 in this TMSCl/KF-mediated desilylation pro-
cess. Thus, the interaction of metal fluoride and/or H2O
with the mild Lewis acidic TMSCl might account for the
readily desilylation of O-TBS ethers.
The effectiveness of this method was demonstrated in a
scale up experiment. Desilylation of (–)-menthol O-TBS
ether 3 in a 15 mmol scale produced the parent (–)-men-
thol in 90% isolated yield after treatment with TMSCl (1.0
equiv) in MeCN (ca. 1.0 M) containing one equivalent of
KF·2H2O for 20 minutes at room temperature (see Ex-
perimental section).
It is noteworthy that the formation of a substantial amount
of corresponding chlorides from the parent alcohols were
observed7 in the cases of primary allylic (i.e. compound
10) or certain benzylic TBS ethers (Equation 3, 16 → 17
+ 18) when one equivalent of TMSCl was used, although
allylic chloride were unstable on silica gel during chroma-
tography and converted to the parent alcohols eventually.
The apparent limitation of this method for the cleavage of
sterically congested O-TBS ether was illustrated in
Equation 4, in which a preferential deblocking (19 → 20)8
of tert-butoxycarbonyl (Boc) protecting group of the
primary amino group was observed.
To ascertain the effectiveness and functional group com-
patibility of this desilylation method, a variety of sub-
strates were subjected to TMSCl-mediated desilylation in
the presence of a stoichiometric amount of KF·2H2O in
MeCN (Table 3). For primary and secondary O-TBS
ethers (compounds 1, 3, 4, 10, 13–15), when one equiva-
lent of TMSCl was used, the desilylation reaction was rap-
id and high yielding. Desilylation of sterically demanding
O-TBS ether proceeded much more slowly (compound 8).
Selective cleavage of primary O-TBS ethers can be
achieved (compounds 5 and 6) by employing a catalytic
amount of TMSCl (0.1–0.2 equiv) in the presence of sec-
ondary O-TBS ethereal functionality. Chemoselective
deprotection of benzylic O-TBS ethers is achievable in the
presence of phenolic O-TBS ether (compounds 7 and 9).
In addition, other commonly used hydroxyl protecting
groups, i.e., O-benzyl, O-methoxymethyl, O-tetrahydro-
OH
Cl
OTBS
TMSCl, KF⋅2H2O
O
O
O
O
O
O
+
MeCN, 1 min
80%
(1 : 1)
16
17
18
Equation 3
Synlett 2006, No. 8, 1165–1168 © Thieme Stuttgart · New York

LETTER
Desilylation of O-tert-butyldimethylsilyl Ether with TMSCI/KF·2H2O in MeCN
1167
Table 3 Desilylation Mediated by TMSCl and KF·2H2O in
O
O
MeCNa (continued)
TMSCl, KF⋅2H2O
MeCN, 30 min
Bn
Bn
O
O
O
BocHN
O
H2N
O
Substrate
Reaction Product (yield, %)
time
62%
OTBS
OTBS
O
19
20
O
O
TBSO
n-C11H23
12
HO
n-C11H23
O
O
Equation 4
5 min
5 min
n-C6H13
n-C6H13
75
It is evident that the in situ generation of hydrogen chlo-
ride from this reagent system alone is less possible ac-
counting for the facile and chemoselective desilylation
process (i.e. the system consisting of aq HCl–MeCN led
to the cleavage of both primary and secondary O-TBS
ethers as well as deblocking of other acid-sensitive pro-
tecting groups, cf. ref. 3o). We assume that the nucleo-
philic activation9 of TMSCl via H2O or KF coordination
(to silicon) leading to a more Lewis acidic pentaco-
ordinated silicon species, which may be responsible for
the facile cleavage of O-TBS ethers. The detailed mecha-
nism of this mild desilylation reaction remains to be
further elucidated.
BnO
OTBS
BnO
OH
6
6
13
90
20 min
40 min
HO
90d
TBSO
14
OH
OTBS
HO
OTHP
HO
OTHP
TBDPSO
TBDPSO
Table 3 Desilylation Mediated by TMSCl and KF·2H2O in
MeCNa
15
67f
a Reactions were run on a scale of 1–2.5 mmol with 1.0 equiv of
TMSCl unless otherwise stated, and all products were confirmed by
comparison with the authentic sample of their parent alcohols.
b Isolated yields.
Substrate
Reaction Product (yield, %)
time
OTBS
OH
c This reaction was performed under reflux.
15 min
n-C11H23
OTs
n-C11H23
OTs
d This reaction was run at 60 °C.
e A catalytic amount of TMSCl (0.1–0.2 equiv) was used.
f About 0.6 equiv of TMSCl were used.
1
85
OTBS
OH
1 min
In conclusion, TMSCl is a mild and efficient Lewis acidic
mediator10 for the effective and chemoselective desilyla-
tion of primary and secondary O-TBS ethers in combina-
tion with a stoichiometric amount of KF·2H2O in MeCN.
The notable features of this method include the generally
rapid reaction, use of inexpensive reagents as well as con-
venient experimental procedure. Therefore, it may find
appropriate applications in practical organic synthesis.
3
4
95
OTBS
OH
1 min
3 h
96b
OTBS
OH
OTBS
OTBS
n-C11H23
OH
n-C11H23
OTBS
OTBS
5
75e
OTBS
OTBS
3 h
6
82e
For flash column chromatography, silica gel (200–300 mesh) and
light petroleum ether (PE, bp 60–90 °C) were used. All solvents
were freshly purified and dried by standard techniques prior to use.
OH
5 min
TBSO
75f
TBSO
1
All desilylated products were characterized by IR and H NMR
7
spectra and directly compared with an authentic sample of their
corresponding parent alcohols. IR spectra were recorded on a
18 h
1
EtO2C OTBS
EtO2C OH
Nicolet FT-170SX spectrometer as liquid films. H NMR spectra
70c
were taken on a Bruker AM-400 spectrometer with TMS as an
internal standard and CDCl3 as solvent.
8
OTBS
OH
1 min
MOMO
MOMO
Representative Procedure for Desilylation with TMSCl and
KF·2H2O
9
90
To a stirred solution of TBS ether 1 (498 mg, 1.0 mmol) in anhyd
MeCN (2 mL) was added powdered KF·2H2O (94 mg, 1.0 mmol),
followed by the addition of freshly distilled TMSCl (0.127 mL, 1.0
mmol) at r.t. After vigorously stirring for 5 min, the reaction mix-
ture was treated with sat. aq NaHCO3 (1 mL) and extracted with
CH2Cl2 (2 × 20 mL). The combined extracts were washed with
H2O, brine, and dried. The solvent was evaporated in vacuo and the
3 min
3 h
OH
OTBS
10
85
THPO
OTBS
THPO
65e
OH
6
6
11
Synlett 2006, No. 8, 1165–1168 © Thieme Stuttgart · New York

1168
Y. Peng, W.-D. Z. Li
LETTER
crude product was purified by column chromatography on silical
gel to afford 326 mg (85%) of alcohol 2, identical in all aspects with
an authentic sample.
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Representative Scale-Up Procedure for Desilylation with
TMSCl and KF·2H2O
To a stirred sloution of TBS ether 3 (4.06 g, 15.0 mmol) in anhyd
MeCN (15 mL) was added powdered KF·2H2O (1.41 g, 15.0 mmol)
in one portion and followed by the addition of freshly distilled
TMSCl (1.91 mL, 15.0 mmol) at r.t. One minute later, TLC showed
a conversion of ca. 80% of starting TBS ether. After stirring for 20
min, the reaction mixture was treated with sat. aq NaHCO3 (5 mL)
and extracted with CH2Cl2 (2 × 50 mL). The combined extracts
were washed with H2O, brine, and dried. The solvent was removed
in vacuo and the crude product was purified by flash chromato-
graphy on silica gel to afford 2.11 g (90%) of parent (–)-menthol.
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We thank the National Natural Science Foundation (Distinguished
Youth Fund 29925204 and Fund 20021001), Fok Ying Tung
Education Foundation (Fund 71012), and Ministry of National
Education (Funds 99114 and 2000-66) for financial support. The
Cheung Kong Scholars program is gratefully acknowledged.
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Synlett 2006, No. 8, 1165–1168 © Thieme Stuttgart · New York