Use of catalytic fluoride under neutral conditions for cleaving silicon-oxygen bonds

Article abstract of DOI:10.1021/jo200848j

This Article describes the development of conditions for cleaving silicon-oxygen bonds using catalytic quantities of fluoride at neutral pH in mixed organic-aqueous solutions that contain buffer. A variety of silicon protecting groups can be removed under these conditions, which show tolerance for acid- and base-sensitive groups. A modified procedure also is presented using catalytic fluoride in anhydrous dimethyl sulfoxide-methanol, which generates primarily volatile silicon byproducts.

Full text of DOI:10.1021/jo200848j

ARTICLE
pubs.acs.org/joc
Use of Catalytic Fluoride under Neutral Conditions for Cleaving
SiliconꢀOxygen Bonds†
Anthony M. DiLauro, Wanji Seo, and Scott T. Phillips*
Department of Chemistry, The Pennsylvania University, University Park, Pennsylvania 16802, United States
S Supporting Information
b
ABSTRACT: This Article describes the development of con-
ditions for cleaving siliconꢀoxygen bonds using catalytic quan-
tities of fluoride at neutral pH in mixed organicꢀaqueous
solutions that contain buffer. A variety of silicon protecting
groups can be removed under these conditions, which show
tolerance for acid- and base-sensitive groups. A modified procedure also is presented using catalytic fluoride in anhydrous dimethyl
sulfoxideꢀmethanol, which generates primarily volatile silicon byproducts.
’ INTRODUCTION
(THF) and as the solid hydrate) is frequently the first reagent
explored.4 Anhydrous TBAF also can be prepared, but in
addition to requiring the use of an inert atmosphere box, it is
both strongly basic and nucleophilic, which can be an advantage
or disadvantage depending on the substrate.7
For silyl ether cleavage reactions, commercial sources of TBAF
are used more often than anhydrous TBAF, but both the solid
and solution forms of commercial TBAF contain water. The
quantity of this water depends on the batch of TBAF, the age of
the reagent, and the conditions under which the reagent
is stored.2,3,8 As a consequence, solutions of TBAF (whether
made from solid TBAF or purchased as a solution) often are
treated with molecular sieves to reduce the water content of
the solution.8
Neutral conditions for cleaving silyl ethers are desirable when
dealing with sensitive substrates, yet most examples of deprotec-
tion conditions are either acidic or basic. TBAF is particularly
troublesome in this regard, since the presence of water in TBAF
creates a basic solution.9,10 Acetic acid frequently is added to
reactions that employ TBAF in an effort to neutralize the base,2,11
but the addition of acetic acid often has the effect of substantially
decreasing the rate of cleavage of the SiꢀO bond.5,12 Moreover,
the quantity of acetic acid needed to neutralize the solution
depends on the amount of base present in the TBAF, which, like
the concentration of water, varies from bottle to bottle. If
rigorously neutral reaction conditions are necessary, then experi-
mentation is required to determine the correct quantity of acetic
acid needed.2 In most cases, however, this level of rigor is not
implemented, and instead the reaction solution remains either
basic or acidic depending on whether too little or too much acetic
acid was added.
During our studies on analyte-responsive polymers, a tert-
butyldimethylsilyl (TBS) end-capped poly(phthalaldehyde)
polymer was designed to depolymerize upon exposure to fluoride
via fluoride-mediated cleavage of the TBS protecting group from
the end of the polymer (Figure 1).1 We were surprised, however,
to find that the polymer depolymerized completely when ex-
posed to only 0.5 equiv of tetrabutylammonium fluoride (TBAF)
in 1000:1 THFꢀphosphate-buffered water (K2HPO4, pH 7.1).1
Traditionally, conditions for cleaving a silyl ether use stoichio-
metric fluoride to obtain complete cleavage of the siliconꢀ
oxygen bond;2ꢀ4 these conditions also typically use pure organic
solvents, not organicꢀaqueous solutions such as those used in
our polymer studies.1 Thus, we reasoned that perhaps the water
was playing a crucial role in enabling complete deprotection
using substoichiometric quantities of fluoride, as noted by
Higashibayashi et al. in their paper on the use of acetic acid to
effect selective cleavage of silyl ethers.5
The aim of this study was to evaluate whether the catalytic,
neutral silyl ether bond cleavage reaction in Figure 1 could be
made into a general procedure for removing silicon protecting
groups. Herein, we describe new conditions for removing silicon
protecting groups using catalytic fluoride.6 These conditions
employ commercially available reagents, do not require exclusion
of air, operate under neutral pH (e.g., pH 7.1) at 23 °C under
buffered conditions, and provide the product of the reaction
cleanly and in high yield. We believe that these conditions will
find use in a variety of contexts, particularly for deprotecting acid-
and base-sensitive substrates and in large-scale reactions where
the cost of the fluoride reagent and/or the effort to remove the
spent fluoride reagent from the product becomes burdensome.
Background on Fluoride-Mediated Cleavage of Silyl Ethers.
Siliconꢀoxygen bonds can be cleaved under a variety of condi-
tions, including those that use acid, base, Lewis acids, heat, and/
or a source of fluoride.2,3 Fluoride-mediated cleavage is one of the
most common methods for effecting this transformation,2,3 and
TBAF (available commercially as a solution in tetrahydrofuran
Other fluoride-based reagents, such as hydrofluoric acid and
HF pyridine, also are used for effecting SiꢀO bond cleaving
3
reactions,2,3 but these reagents render the reaction conditions
Received: April 26, 2011
Published: August 16, 2011
r
2011 American Chemical Society
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Figure 1. An analyte-responsive polymer that depolymerizes completely when exposed to 0.5 equiv of TBAF in mixtures of THF and buffered water.1
either acidic or basic. Nonacidic or nonbasic reagents are
available for removing silicon protecting groups (e.g., tris-
(dimethylamino)sulfonium difluorotrimethylsilicate (TASF),13ꢀ15
tetrabutylammonium tetra(tert-butyl alcohol)-coordinated fluor-
ide (TBAF(tBuOH)4),16 and tetrabutylammonium triphenyldi-
fluorosilicate (TBAT)10,17), with the caveat that such reagents
either must be freshly prepared, require refluxing reaction
conditions, are hygroscopic, and/or are expensive when
purchased commercially.
This latter point on the cost of reagents is especially im-
portant when reactions are conducted on large scale because
a stoichiometric quantity of a fluoride reagent is used to
effect complete deprotection. Moreover, the use of stoichio-
metric reagents leads to the presence of stoichiometric
byproducts that must be separated from the product of the
reaction. This purification process can be laborious, especially
when phase-transfer reagents such as tetraalkylammonium
reagents (e.g., TBAF) are used.18 Hence, the catalytic depro-
tection conditions described herein may be of value in a
variety of contexts.
’ RESULTS
Deprotection of R3SiOR Using Catalytic TBAF. To test
Figure 2. Demonstration of the catalytic effects of TBAF on (a) the
whether the conditions in Figure 1 could be made more general
for small molecules, we dissolved tert-butyldimethylsilyl4 (TBS)-
conversion of 1 to 2 under neutral reaction conditions. (b) The
relationship between reaction time and the quantity of 1 remaining
protected benzyl alcohol (1) (0.1 M) in THFꢀphosphate buffer
in the reaction mixture. The experiments were performed in tripli-
(pH 7.1, 0.1 M) at 23 °C and exposed it to various quantities of
cate and all data are included on the graph. The percent conversion
of 1 to 2 was determined by integrating peak areas in HPLC
TBAF, ranging from 0 equiv to 1.1 equiv (Figure 2). Figure 2
shows that complete removal of the silicon protecting group can
be effected even with substoichiometric quantities of fluoride. In
addition, the time required for complete conversion of 1 to 2 is
inversely proportional to the number of equivalents of fluoride
added to the reaction mixture. Background hydrolysis of the
SiꢀO bond by buffered water does not account for these
observations (Figure 2b).
Effect of pH, Buffer Concentration, and the Quantity of
Water on the Deprotection Reaction. The reaction mixtures
depicted in Figure 2 remained at approximately pH 7 throughout
the course of the reaction.19 We found that solutions of TBAF in
0.0 M, 0.1 M, 0.25 M, and 0.5 M phosphate buffer (pH 7.1) can
be used instead of solutions of TBAF in 0.1 M phosphate buffer
with no noticeable effect on the rate of the deprotection reaction
(Figure S1, Supporting Information); such conditions may be
necessary for substrates that are particularly sensitive to fluctua-
tions in pH. Likewise, different pH values (e.g., pH 6.5, 7.0, 7.5,
and 8.0) provide rates of reaction that are identical to the
standard pH 7.1 conditions, making this reaction useful for
substrates that are especially sensitive to either acid or base
(Figure S2, Supporting Information).
chromatograms. Percent conversion = (areacompound 1/(areacompound 1
areacompound 2)) ꢁ 100%.
+
efficient deprotection reaction (Figure 3). For example, when 1 is
treated with 0.5 equiv of TBAF for 6 h under the reaction
conditions, conversion to 2 occurs equally well when water is
present in quantities ranging from 0.6ꢀ1.2% in THF.20,21
However, as the quantity of water in the reaction mixture
increases to g1.4%, the percent conversion at 6 h decreases
dramatically.22
Effect of the Reaction Vessel on the Deprotection Reac-
tion. Because the reaction conditions employ only a catalytic
quantity of fluoride, the type of reaction vessel becomes im-
portant to the success of the reaction. The results shown in
Figures 2 and 3 were obtained from reactions run in polypropy-
lene centrifuge tubes, which, unlike glass, should not sequester
trace quantities of fluoride from solution. When deprotection
reactions of 1 were conducted using 0.1 equiv of TBAF in typical
Pyrex round-bottomed flasks, the results were inconsistent:
several experiments showed decreased rates of deprotection of 1
in comparison to identical reactions run in polypropylene centrifuge
tubes, while others showed indistinguishable rates. Because of this
variation in reaction rates, we recommend using polypropylene
reaction vessels for catalytic cleavage reactions of SiꢀO bonds.
The presence of phosphate buffer would do little to control the
pH of the reaction mixture in the absence of water, and we found
that there is a threshold level of water that is necessary for an
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Figure 4. Effect of the silicon protecting group on the rate of cleavage of
the SiꢀO bond. (a) The reaction conditions for deprotection of
different silicon protecting groups. The concentration of the protected
benzyl alcohol was 0.1 M in 100:1 THFꢀbuffer (K2HPO4, pH 7.1). (b)
Reaction rates were determined using HPLC by measuring the con-
sumption of the starting material relative to the formation of product.
The experiments were repeated three times.
Figure 3. EffectoftheratioofTHFꢀwater on the percent conversion of 1
to 2 after 6 h of reaction time.21 Percent conversion of 1 to 2 was
determined by integration of peak areas in HPLC chromatograms. Percent
conversion = (areacompound 1/(areacompound 1 + areacompound 2)) ꢁ 100.
Table 1. Deprotection of Silyl Ether Protecting Groups in
Complex Substratesa
A General Deprotection Procedure. Taken together, the
results above have led to the following general silyl ether cleavage
procedure:23 (a) Preparation of a 3.3 M buffered TBAF solution:
Tetrabutylammonium fluoride hydrate (0.24 g, 0.90 mmol) was
dissolved in anhydrous tetrahydrofuran (90 μL). The resulting
solution was sonicated for 10 min. Aqueous dibasic potassium
phosphate (K2HPO4) (0.1 M, pH 7.1, 180 μL) was added to the
TBAF solution, and the resulting mixture was sonicated for an
additional 3 min. No precautions were employed to exclude air.
(b) Deprotection of 1: Buffered tetrabutylammonium fluoride
solution (50 μL, 3.3 M, 0.16 mmol, 0.5 equiv) was added to
a solution of TBS-protected benzyl alcohol (1) (73 mg,
0.33 mmol, 1 equiv) in tetrahydrofuran (3.3 mL, anhydrous)
in a 15-mL polypropylene tube. The polypropylene tube was
capped, and the reaction mixture was stirred at 23 °C for 6 h, at
which point the solvent was removed under reduced pressure.
The product was purified using silica gel flash column chroma-
tography (20% ethyl acetate in hexanes) to provide benzyl
alcohol (2) as a colorless oil (35 mg, 98%).
Application to Other Silicon Protecting Groups. These
neutral, catalytic conditions for cleaving SiꢀO bonds extend to
other silicon protecting groups as well. Deprotection reactions
using0.1 equiv ofTBAF in100:1 THFꢀbuffered water(K2HPO4,
pH 7.1) (0.1 M in substrate, 23 °C) followed pseudo-first-order
kinetics with rate constants that are consistent in relative
magnitude to known rates of fluoride-mediated deprotection of
triethylsilyl (TES),24 TBS, triisopropylsilyl (TIPS),25 and tert-
butyldiphenylsilyl (TBDPS)26 groups (Figure 4).1,27 Diphenyl-
methylsilyl (DPMS) (6)-28 and triphenylsilyl (TPS) (7)-pro-
tected benzyl alcohol were deprotected completely under the
same reaction conditions in less than 5 min. The disadvantage of
the catalytic reaction conditions, particularly when only 0.1 equiv
of TBAF are used, is the slow reaction time for bulky silicon
protecting groups; for example, removal of the TBDPS protect-
ing group required ∼4 days to reach completion.
a The compounds (0.1 M) were deprotected at 23 °C using 0.5 equiv of
TBAF in 100:1 THFꢀbuffered water (K2HPO4, pH 7.1).
Application to Complex Substrates. These SiꢀO cleavage
conditions were evaluated in the context of more complex
substrates as well (Table 1). The data in Table 1 demonstrates
that these neutral, catalytic deprotection conditions are capable
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our modified anhydrous conditions is that base arising from
adventitious water is not buffered, and therefore the conditions
may not be compatible with all base-sensitive substrates.
’ CONCLUSION
The new silyl ether cleavage conditions described in this
Article are mild (pH 7.1, 23 °C) and use as little as 0.1 equiv
of either TBAF or CsF. These catalytic deprotection conditions
should prove useful both for acid- and base-sensitive substrates
and for large-scale reactions in which cost and ease of purification
(i.e., removal of the source of fluoride) are both a primary
concern. Moreover, the studies described herein may have impli-
cations in standard TBAF-mediated deprotection reactions that
Figure 5. HPLC chromatograms of (a) TBDPS-protected benzyl
alcohol (5) and (b) the UV-active products at >95% deprotection of
5. Compound 5 was deprotected at 23 °C using 0.1 equiv of TBAF in
100:1 THF-buffered water (K2HPO4, pH 7.1).
use commercial sources of TBAF xH2O. Mechanistic studies
3
to investigate this catalytic SiꢀO bond cleavage reaction are
in progress.
of cleaving SiꢀO bonds selectively in the presence of functional
groups that are sensitive to base (8, 10)29 and acid (10, 14).
Improving the Deprotection Reaction
’ EXPERIMENTAL SECTION
a. Determining the Fate of Silicon. We used HPLC to probe
the fate of silicon during the deprotection of TBDPSOBn (5);
our goal was to devise a straightforward strategy for separating
the desired product from the silicon byproducts once they were
known. Figure 5 shows that the dominant silicon byproduct of
this reaction is silanol 18 (TBDPSOH); no silyl fluoride was
observed by HPLC, and only a trace quantity of TBDPS2O (19)
was present. To determine whether the observed silanol 18 was
the result of HPLC-mediated hydrolysis, we prepared an authen-
tic sample of TBDPS2O and demonstrated that it does not hydrolyze
under the HPLC conditions used for analysis (Figure S5).
This observation indicates that the HPLC chromatogram in
Figure 5 is an accurate representation of the quantities of
TBDPS2O and silanol 18 in the reaction mixture and not a
result of the conditions used for analysis.
b. A Modified Procedure That Generates Volatile Silicon
Byproducts. As demonstrated in Figure 3, water is crucial to the
success of this catalytic deprotection reaction; therefore, we
suspected that an alcohol could serve the same purpose. By
using an alcohol (e.g., methanol) instead of water, we reasoned
that the resulting silyl ether byproducts would be volatile and
hence could be separated easily from the product of the reaction.
To test this theory, we conducted the following experiment:
TBDPSOBn (5) (0.1 M) in 100:1 anhydrous DMSOꢀ
anhydrous MeOH was exposed to 0.1 equiv of CsF at 23 °C.
After 20 h, HPLC analysis revealed that >95% of 5 had been
converted to BnOH (2).30 This reaction time is approximately
4.8ꢁ shorter than that observed with the TBAF under THF-
buffered water conditions (Figure 4). The silicon byproducts for
the deprotection of 5 in DMSOꢀMeOH are tBuPh2SiOMe
(which is volatile and easily removed by rotary evaporation),
tBuPh2SiOH (which likely was formed from the presence of
trace quantities of water), and (tBuPh2)2SiO. TBSOBn (1) was
also tested under these conditions and provided similar results.
As an added advantage, CsF is easier to work with than solid
TBAF because CsF can be flame-dried under vacuum, stored in a
160 °C oven, and manipulated in air. Solid, anhydrous TBAF can
be prepared but is extremely hygroscopic and typically requires
the use of inert atmosphere boxes and rigorously anhydrous
reaction conditions to avoid adsorption of water.7 Likewise,
commercial TBAF cannot be dried at elevated temperatures
under vacuum, because it undergoes a Hoffman elimination to
yield butene, tributylamine, and bifluoride.7,9,31 The disadvantage of
General Experimental Methods. All reactions were performed
in polypropylene copolymer centrifuge tubes under air unless otherwise
noted. Air- and moisture-sensitive liquids were transferred by
syringe. Organic solutions were concentrated by rotary evaporation
(24ꢀ40 mmHg) at ambient temperature, unless otherwise noted.
Benzyl alcohol, tetrabutylammonium fluoride hydrate, potassium phos-
phate dibasic, and all other reagents were purchased commercially and
were used as received unless otherwise noted. Residual water was
removed from cesium fluoride according to the procedure of Corriu,
Moreau, and Pataud-Sat.32 The silicon-protected benzyl alcohols were
prepared according to the following known procedures: TBS-protected
benzyl alcohol (1), Corey and Venkateswarlu;4 TES-protected benzyl
alcohol (3), Oppolzer, Snowden, and Simmons;24 TIPS-protected
benzyl alcohol (4), Cunico and Bedell;25 TBDPS-protected benzyl
alcohol (5), Hanessian and Lavallee;26 DPMS-protected benzyl alcohol
(6), Denmark, Hammer, Weber, and Habermas;28 TPS-protected
benzyl alcohol (7), Kocienski.3 Flash column chromatography was
performed as described by Still, Kahn, and Mitre,33 employing silica
gel (60-Å pore size, 32ꢀ63 μm, standard grade, Dynamic Adsorbents).
Thin layer chromatography was carried out on Dynamic Adsorbents
silica gel TLC (20 ꢁ 20 w/h, F-254, 250 μm).
Proton nuclear magnetic resonance (1H NMR) spectra were re-
corded at 25 °C. Proton chemical shifts are expressed in parts per million
(ppm, δ scale) and are referenced to tetramethylsilane ((CH3)4Si, 0.00
ppm) or to residual protium in the solvent (C4HD7O, 3.58 ppm and
1.73 ppm). Data are represented as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or
multiple resonances), integration, and coupling constant (J) in hertz.
Carbon nuclear magnetic resonance spectra (13C NMR) were recorded
at 25 °C. Carbon chemical shifts are expressed in parts per million (ppm,
δ scale) and are referenced to the carbon resonances of the NMR solvent
(CDCl3, δ 77.0, or tetrahydrofuran-d8, δ 67.6 ppm and 25.4 ppm).
HPLC analysis was performed using a reversed-phase phenyl-hexyl
column. The column was equilibrated at 1:9 acetonitrileꢀwater at
1 mL/min flow rate, and, after injection of the sample, the gradient
was ramped to 9:1 acetonitrileꢀwater over 15 min. This solvent ratio
was then run for an additional 3 min for a total run time of 18 min.
General Procedure for Preparing Buffered TBAF Solu-
tions. a. Preparation of a 6.7 M Buffered TBAF Solution. Tetrabuty-
lammonium fluoride hydrate (0.48 g, 1.8 mmol) was dissolved in
anhydrous tetrahydrofuran (90 μL). The resulting solution was soni-
cated for 10 min. Potassium phosphate buffer (0.1 M, pH 7.1, 180 μL)
was added to the TBAF solution, and the entire mixture was sonicated
for an additional 3 min. No precautions were employed to exclude air.
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Table 2
Table 3
molarity of buffered
mass (and millimoles) of tetrabutylammonium
THFꢀbuffer ratio
solution molarity, M
volume of solution used, μL
TBAF solution, M
fluoride hydrate used
425:1
307:1
250:1
220:1
167:1
141:1
84:1
12.8
9.1
11.7
16.2
20.1
22.5
30
12.8
9.1
7.5
5.0
4.3
3.3
2.5
2.1
1.7
0.67
0
0.90 g (3.3 mmol)
0.65 g (2.5 mmol)
0.54 g (2.1 mmol)
0.36 g (1.4 mmol)
0.30 g (1.1 mmol)
0.24 g (0.9 mmol)
0.18 g (0.69 mmol)
0.15 g (0.57 mmol)
0.12 g (0.45 mmol)
0.048 g (0.18 mmol)
0 g (0 mmol)
7.5
6.67
5.0
4.25
2.5
35.4
60
72:1
2.13
1.67
0.67
70.5
90
56:1
23:1
222
fluoride solution (650 μL from the 0.67 M solution, 0.43 mmol fluoride,
0.1 equiv fluoride) was added to the THF solution, the screw cap was
added to the polypropylene tube, and the reaction mixture was stirred at
23 °C. The reaction was complete after 42 h, at which point the reaction
vessel was cooled to ꢀ78 °C to freeze the water in the mixture. The THF
was decanted, and the remaining aqueous reaction mixture was then
warmed to 23 °C. The pH of the aqueous solution was measured using
pH paper and was found to be in a range of pH 6.9ꢀ7.2.
b. Preparation of 12.8 M, 9.1 M, 7.5 M, 5.0 M, 4.3 M, 3.3 M, 2.5 M,
2.1 M, 1.7 M, 0.7 M, and 0 M Buffered TBAF Solutions. Identical
procedures were used as described above for the preparation of a 6.7 M
buffered TBAF solution, with the exception that the quantity of tetra-
butylammonium fluoride hydrate used to make each solution varied as
shown in Table 2.
c. Preparation of 3.3 M Buffered TBAF Solution with 0.0 M, 0.25 M,
and 0.50 M Buffer. Identical procedures were used as described above for
the preparation of a 3.3 M buffered TBAF solution, with the exception
that the initial concentration of the potassium phosphate buffer solution
used were 0.0 M, 0.25 M, and 0.5 M.
General Procedure for Deprotecting R3SiOBn Using 0.1 Equiv
TBAF. The procedure described above for deprotecting TBSOBn (1)
using 0.1 equiv of TBAF was repeated for TESOBn (3), TIPSOBn (4),
TBDPSOBn (5), DPMSOBn (6), and TPSOBn (7). The progress of
the reaction was monitored by 1H NMR.
d. Preparation of 3.3 M Buffered TBAF Solution with pH 6.5, 7.0, 7.5,
and 8.0 Buffer. Identical procedures were used as described above for the
preparation of a 3.3 M buffered TBAF solution, with the exception that
the initial pH values of the potassium phosphate buffer solution used
were pH 6.5, 7.0, 7.5, and 8.0.
General Procedure for the Deprotection of TBSOBn (1).
a. Deprotection of TBSOBn (1) Using 1.1 Equiv of TBAF. To a 15-mL
polypropylene tube charged with a magnetic stirrer were added TBS-
protected benzyl alcohol (1) (66 mg, 0.3 mmol, 1.0 equiv) and
anhydrous tetrahydrofuran (3.3 mL). The buffered tetrabutylammo-
nium fluoride solution (50 μL from the 6.7 M solution, 0.33 mmol
fluoride, 1.1 equiv fluoride) was added to the THF solution, the screw
cap was added to the polypropylene tube, and the reaction mixture was
stirred at 23 °C. The reaction was monitored by HPLC and was
performed in triplicate.
b. Deprotection of TBSOBn (1) Using 0.53, 0.28, 0.1, and 0 Equiv of
TBAF. Identical procedures were used as described above in part a, with
the exception that different solutions of buffered TBAF were used as
follows: 0.53 equiv (3.3 M buffered TBAF); 0.28 equiv (1.7 M buffered
TBAF; 0.10 equiv (0.67 M buffered TBAF); 0 equiv (0 M buffered
TBAF).
c. Deprotection of TBSOBn (1) Using THFꢀBuffer Ratios of 425:1,
307:1, 250:1, 220:1, 167:1, 141:1, 84:1, 72:1, 56:1, and 23:1. Identical
procedures were used as described above in part a, with the exception
that 0.5 equiv (0.15 mmol) of TBAF was used, and different volumes and
different concentrations of buffered TBAF solutions were used as shown
in Table 3.
Synthesis of Complex Substrate 8. To a flame-dried round-
bottom flask charged with a magnetic stirrer were added N-(9-
fluorenylmethoxycarbonyl)-L-phenylalanine (0.60 g, 1.6 mmol, 1.1 equiv),
L-serine benzyl ester hydrochloride (0.33 g, 1.4 mmol, 1 equiv), O-
benzotriazole-N,N,N0,N0-tetramethyluronium hexafluorophosphate (HBTU)
(0.70 g, 1.8 mmol, 1.3 equiv), and anhydrous methylene chloride
(15 mL). The flask was placed under an atmosphere of nitrogen, and
N,N-diisopropylethylamine (1.2 mL, 7.1 mmol, 5 equiv) was added. The
reaction mixture was stirred at 23 °C overnight and then was diluted with
ethyl acetate and washed with 0.1 M HCl, followed by 10% aqueous
sodium bicarbonate solution and brine. The organic layer was collected
and dried over magnesium sulfate, and the solution was filtered and
concentrated. The product was purified using silica gel flash column
chromatography using 50% ethyl acetate in hexanes to provide N-(9-
fluorenylmethoxycarbonyl)-L-phenylalanine-L serine benzyl ester (9)34
as a white solid (0.72 g, 1.3 mmol, 90%). mp 234ꢀ239 °C; IR (cmꢀ1
)
3300, 1740, 1690, 1640; 1H NMR (THF-d8) δ 7.76 (d, 2H, J = 7.5), 7.59
(t, 2H, J = 5.3), 7.38ꢀ7.16 (m, 14H), 6.87 (d, 1H, J = 8.6), 5.16 (s, 2H),
4.61 (s, 1H), 4.53 (m, 1H), 4.20ꢀ4.15 (m, 3H), 3.87 (m, 1H), 3.74 (m,
1H), 3.11 (m, 1H), 2.90 (m, 1H); 13C NMR (THF-d8) δ 172.1, 171.1,
156.8, 145.3, 145.3, 142.2, 138.7, 137.3, 129.1ꢀ126.0, 120.5, 63.1, 56.8,
55.8, 54.9, 48.2; TOF MS (ESI) m/z 565 (100 MH+). HRMS (ESI)
Calcd for C34H33N2O6 (M + H+): 565.2339. Found: 565.2341.
To a flame-dried round-bottom flask were added N-(9-fluorenyl-
methoxycarbonyl)-L-phenylalanine-L-serine benzyl ester (9) (0.33 g,
0.58 mmol, 1 equiv), imidazole (0.10 g, 1.5 mmol, 2.5 equiv), and
anhydrous dimethylformamide (15 mL). The flask was placed under an
argon atmosphere, and the reaction mixture was cooled to 0 °C.
Chlorotriethylsilane (0.11 g, 0.70 mmol, 1.2 equiv) was added to the
flask dropwise via syringe, and the reaction mixture was warmed to 23 °C
over 1 h and then allowed to stir overnight. The reaction mixture was
diluted with dichloromethane, and the organic layer was washed with
0.1 M HCl (1 ꢁ 30 mL), followed by water (1 ꢁ 30 mL) and brine (1 ꢁ
30 mL). The organic layer was dried over sodium sulfate, filtered, and
concentrated. The crude product was purified using silica gel flash
Procedure for Measuring the pH of the Deprotection
Reaction Mixture. Tetrabutylammonium fluoride hydrate (0.48 g,
1.8 mmol) was dissolved in 1.8 mL of potassium phosphate buffer
(0.1 M, pH 7.1, 180 μL). The pH of the solution was found to be 7.1
using a pH meter.
To a 50-mL polypropylene tube charged with a magnetic stirrer were
added TBS-protected benzyl alcohol (1) (0.95 g, 4.3 mmol, 1 equiv) and
anhydrous tetrahydrofuran (43 mL). The buffered tetrabutylammonium
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The Journal of Organic Chemistry
ARTICLE
column chromatography using 20% ethyl acetate in hexanes to yield
N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine-O-(triethylsilyloxy)-
L-serine benzyl ester (8) as a white solid (0.25 g, 0.37 mmol, 63%). mp:
137ꢀ140 °C; IR (cmꢀ1) 3290, 1740, 1690, 1650; 1H NMR (CDCl3) δ
7.75 (d, 2H, J = 7.1), 7.52 (t, 2H, J = 7.6), 7.40ꢀ7.20 (m, 14H), 6.61 (br
s, 1H), 5.48 (br s, 1H), 5.16 (s, 2H), 4.65 (d, 2H, J = 5.4), 4.51 (s, 1H),
4.40 (t, 1H, J = 7.0), 4.27 (s, 1H), 4.16 (t, 1H, J = 6.1), 4.05 (d, 1H, J =
9.8), 3.76 (d, 1H, J = 10), 3.09 (s, 2H), 0.85 (t, 9H, J = 5.3) 0.49 (q, 6H,
J = 5.3); 13C NMR (CDCl3) δ 170.7, 169.8, 155.8, 150.6, 143.9, 141.4,
136.4, 135.4, 129.6, 128.6, 128.5, 128.2, 125.2, 120.0, 107.3, 67.4, 63.1,
56.9, 54.5, 47.1, 38.9, 6.7, 4.3; TOF MS (ESI) m/z 679 (100 MH+).
HRMS (ESI) Calcd for C40H47N2O6Si (M + H+): 679.3203. Found:
679.3207.
Synthesis of Complex Substrate 16. To a flame-dried round-
bottom flask charged with a magnetic stirrer was added 2,2,2-trifluoro-1-
phenylethanol (17) (0.20 g, 1.4 mmol), imidazole (0.19 g, 2.8 mmol),
tert-butyl(chloro)dimethylsilane (0.21 g, 1.4 mmol), and anhydrous
acetonitrile (1 mL). The flask was placed under an argon atmosphere
and allowed to stir overnight. The reaction mixture was partitioned over
dichloromethane (10 mL) and 0.1 M HCl (10 mL). The aqueous layer
was separated and washed with dichloromethane (2 ꢁ 10 mL). The
organic layers were combined, dried over sodium sulfate, filtered, and
concentrated. The crude product was purified with silica gel flash
column chromatography using 100% pentane to yield tert-butyldimethyl-
(2,2,2-trifluoro-1-phenylethoxy)silane (16) as a clear oil (0.20 g,
0.69 mmol, 62%). IR (cmꢀ1) 1260, 1170, 1120, 850; 1H NMR
(CDCl3) δ 7.44 (m, 2H), 7.38 (m, 3H), 4.91 (q, 1H, J = 7.2), 0.89 (s,
9H), 0.11 (s, 3H), ꢀ0.03 (s, 3H); 13C NMR (CDCl3) δ 135.7, 129.2,
128.4, 127.8, 73.8, 25.6, 18.3, ꢀ5.0, ꢀ5.2; TOF MS (ESI) m/z 233 (29
[M ꢀ tBu]+). HRMS (ESI) Calcd for C10H12F3OSi ([M ꢀ tBu]+):
233.0610. Found: 233.0619.
Deprotection of Complex Substrates. a. Deprotection of 8.
To a 1.7-mL polypropylene microcentrifuge tube charged with a
magnetic stirrer were added N-(9-fluorenylmethoxycarbonyl)-
L-phenylalanine-O-(triethylsilyloxy)-L-serine benzyl ester (8) (0.04 g,
0.06 mmol, 1 equiv) and anhydrous tetrahydrofuran (0.65 mL). Buf-
fered tetrabutylammonium fluoride solution (9.7 μL from the 3.3 M
solution, 0.05 mmol fluoride, 0.5 equiv) was added to the THF solution,
the cap was affixed to the polypropylene tube, and the reaction mixture
was stirred at 23 °C. The reaction was complete after 3 h, at which point
the crude material was loaded directly onto a silica gel flash column.
Chromatography (30:70 ethyl acetateꢀhexanes, increasing to 50:50
ethyl acetateꢀhexanes) provided N-(9-fluorenylmethoxycarbonyl)-
L-phenylalanine-L-serine benzyl ester (9)34 (0.02 g, 0.04 mmol, 63%).
b. Deprotection of 10. To a 1.7-mL polypropylene microcentrifuge
tube charged with a magnetic stirrer were added acetic acid
3S-[benzyl-(9H-fluoren-9-ylmethoxycarbonylamino)-2R-tert-butyloxy-
carbonylamino-5-trimethylsilylpent-4-ynyl] ester (10)35 (10 mg,
16 μmol, 1 equiv) and anhydrous tetrahydrofuran (0.2 mL). Buffered
tetrabutylammonium fluoride solution (2.3 μL from a 3.3 M solution,
7.6 μmol fluoride, 0.5 equiv) was added to the THF solution, the cap was
affixed to the polypropylene tube, and the reaction mixture was stirred at
23 °C. The reaction was complete after 5 min, at which point the crude
material was loaded directly onto a silica gel flash column. Chromatog-
raphy (80:20 hexanesꢀethyl acetate) provided acetic acid 3S-[benzyl-
(9H-fluoren-9-yl-methoxycarbonylamino)-2R-tert-butyloxycarbonyla-
minopent-4-ynyl] ester (11) as a white solid (8.4 mg, 15 μmol, 95%).
mp: 226ꢀ231 °C; IR (cmꢀ1) 3280, 2120, 1705; 1H NMR (CDCl3) δ
7.67 (d, 2H J = 7.4), 7.30 (s, 8H), 7.12ꢀ7.08 (m, 3H), 5.33 (d, 1H, J = 9),
5.04 (d, 1H, J = 9.8), 4.62ꢀ4.00 (m, 8H), 2.33 (s, 1H), 1.41 (s, 9H); 13C
NMR (CDCl3) δ 170.8, 158.2, 155.5, 143.8, 141.2, 138.1, 128.6ꢀ125.0,
120.0, 98.0, 80.0, 78.5, 68.8, 64.4, 49.9, 48.6, 47.2, 28.5, 21.0; TOF MS
(ESI) m/z 569 (88 MH+). HRMS (ESI) Calcd for C34H37N2O6 (M +
H+): 569.2652. Found: 569.2660.
c. Deprotection of 12. To a 1.7-mL polypropylene microcentrifuge
tube charged with a magnetic stirrer were added 1-(2-azidophenyl)-
4-(tert-butyldimethylsilyloxy)-2-butyn-1-one (12) (11 mg, 36 μmol,
1 equiv) and anhydrous tetrahydrofuran (0.35 mL). Buffered tetrabu-
tylammonium fluoride solution (5.3 μL from the 3.3 M solution,
18 μmol fluoride, 0.5 equiv) was added to the THF solution, the cap
was affixed to the polypropylene tube, and the reaction mixture was
stirred at 23 °C. The reaction was complete after 18 h, at which point the
crude material was loaded directly onto a silica gel flash column.
Chromatography (20:80 ethyl acetateꢀhexanes, increasing to 50:50
ethyl acetateꢀhexanes) provided 1-(2-azidophenyl)-4-(hydroxy)-2-bu-
tyn-1-one (13) as an orange solid (5.6 mg, 0.03 mmol, 78%). mp
164ꢀ167 °C; IR (cmꢀ1) 3260, 2290, 2120, 1720; 1H NMR (CDCl3) δ
7.77 (m, 2H), 7.70 (t, 1H, J = 7.3), 7.42 (t, 1H, J = 7.7), 4.98 (s, 2H), 2.69
(b, 1H); 13C NMR (CDCl3) δ 176.3, 148.1, 141.2, 136.1, 129.2, 128.5,
126.3, 113.3, 57.0, 32.1; TOF MS (API) 202.1 (100, MH+). HRMS
(ESI) Calcd for C10H8N3O2 (M + H+): 202.0590. Found: 202.0599.
d. Deprotection of 14. To a 1.7-mL polypropylene microcentrifuge
tube charged with a magnetic stirrer were added 3-methyl 3-(1-(tert-
butoxycarbonylamino)-2-methylpropyl)-5-((tert-butyldimethylsilyloxy)-
(5-methyl-2-(triisopropylsilyloxy)phenyl)methyl)isoxazole-4-carboxylate
(14) (18 mg, 26 μmol, 1 equiv) and anhydrous tetrahydrofuran
(0.25 mL). Buffered tetrabutylammonium fluoride solution (3.9 μL
from a 3.33 M solution, 0.013 mmol fluoride, 0.5 equiv) was added to the
THF solution, the cap was affixed to the polypropylene tube, and the
reaction mixture was stirred at 23 °C. The reaction was complete after
24 h, at which point the crude material was purified directly using silica gel
flash chromatography (15:85 ethyl acetateꢀhexanes, increasing to 30:70
ethyl acetateꢀhexanes) to provide methyl 3-(1-(tert-butoxycarbonylamino)-
2-methylpropyl)-5-((hydroxy)(2-hydroxy-5-methylphenyl)methyl)-
isoxazole-4-carboxylate (15) as a clear oil (10 mg, 24 μmol, 95%). IR
(cmꢀ1) 3250, 1710, 1680; 1H NMR (CDCl3) δ 7.98 (b, 1H), 7.02 (d,
1H, J = 8.1), 6.78 (m, 2H), 6.39 (b, 1H), 5.32 (m, 1H), 5.17 (m, 1H),
3.91 (s, 3H), 2.22 (s, 3H), 2.07 (m, 1H), 1.42 (s, 9H), 0.98ꢀ0.83 (m,
6H); 13C NMR (CDCl3) δ 178.0, 163.7, 163.2, 155.8, 153.2, 130.9,
129.7, 128.0, 122.4, 117.3, 108.3, 80.1, 68.2, 52.8, 32.6, 28.5, 20.7,
20.0, 17.1; TOF MS (ESI) m/z 435 (100 MH+). HRMS (ESI) Calcd
for C22H31N2O7 (M + H+): 435.2131. Found: 435.2150.
e. Deprotection of 16. To a 1.7-mL polypropylene microcentrifuge
tube charged with a magnetic stirrer was added tert-butyldimethyl(2,2,2-
trifluoro-1-phenylethoxy)silane (16) (41 mg, 0.14 mmol, 1 equiv) and
anhydrous tetrahydrofuran (1.4 mL). Buffered tetrabutylammonium
fluoride solution (21 μL from 3.3 M solution, 0.07 mmol) was added to
the THF solution, the cap was affixed to the polypropylene tube, and the
reaction mixture was stirred at 23 °C. The reaction was complete after 2 h,
at which point the crude material was loaded directly onto a silica gel flash
column. Chromatography (10:90 ethyl acetateꢀhexanes) provided 2,2,2-
trifluoro-1-phenylethanol36 (17) as a clear oil (24 mg, 0.14 mmol, 96%).
Cesium Fluoride Deprotection Conditions. a. Preparation
of a 0.67 M Cesium Fluoride Solution. Cesium fluoride (27 mg,
0.18 mmol) was dissolved in anhydrous dimethyl sulfoxide (90 μL).
The resulting solution was sonicated for 10 min. Anhydrous methanol
(180 μL) was added to the CsF solution, and the entire mixture was
sonicated for an additional 3 min. No precautions were employed to
exclude air.
b. Deprotection of TBSOBn (1). To a 15-mL polypropylene tube
charged with a magnetic stirrer were added TBS-protected benzyl
alcohol (1) (73 mg, 0.33 mmol, 1 equiv) and anhydrous dimethyl
sulfoxide (3.3 mL). The cesium fluoride solution (50 μL from a 0.67 M
solution, 33 μmol fluoride, 0.1 equiv) was added to the DMSO solution,
the screw cap was added to the polypropylene tube, and the reaction
mixture was stirred at 23 °C. The reaction was monitored by HPLC.
Note: The procedure for deprotecting TBDPSOBn (5) is identical to
the procedure for deprotecting 1.
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The Journal of Organic Chemistry
ARTICLE
’ ASSOCIATED CONTENT
(16) Kim, D. W.; Jeong, H-J.; Lim, S. T.; Sohn, M.-H. Angew. Chem.
2008, 120, 8352–8354.
(17) For examples of the use of TBAT in deprotection reactions, see
(a) Coombs, T. C.; Huang, W.; Garnier-Amblard, E. C.; Liebeskind, L. S.
Organometallics. 2010, 29, 5083–5097. (b) Rogness, D. C.; Larock, R. C.
J. Org. Chem. 2010, 75, 2289–2295.
(18) Kaburagi, Y.; Kishi, Y. Org. Lett. 2007, 9, 723–726.
(19) The pH value of the aqueous portion of the solution before
deprotection of 1 was 7.1 (measured using a pH meter). After 1 was
converted completely to 2, the pH value of the aqueous portion of the
reaction mixture was 6.9ꢀ7.2 (measured using pH paper; see Experi-
mental Section for details).
S
Supporting Information. Characterization data for all
b
new compounds, and tables of data for reaction rates. This
material is available free of charge via the Internet at http://
pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: sphillips@psu.edu.
(20) We used a single batch of solid TBAF xH2O for the experi-
3
ments shown in Figures 2 and 3. This batch contained TBAF 1.8H2O,
as determined by elemental analysis.
3
’ ACKNOWLEDGMENT
(21) The total quantity of water in each experiment shown in
Figure 3 was calculated from the sum of the number of moles of water
in: TBAF + THF + water added with the phosphate buffer. Since 0.5
equiv of TBAF were used in each experiment, the TBAF contributed 299
μmol of water. Karl Fischer titration of the THF used in the experiments
revealed 11.41 ppm water, which indicates that the THF contributed 2.1
μmol of water. These sources of water provided a baseline level to which
we added more water by varying the concentration and volume of
buffered TBAF solution that was added to the reaction mixture.
(22) A similar observation was noted by Hogrefe et al. in ref 8 when
using stoichiometric quantities of TBAF to effect deprotection of a
silicon protecting group.
(23) These deprotection conditions resemble known conditions
that use NH4F (14 equiv) in MeOH (60 °C) (Zhang, W.; Robins,
M. J. Tetrahedron Lett. 1992, 33, 1177–1180). The deprotection
conditions described herein differ from the method of Zhang and
Robins in several ways: the conditions reported herein (i) use catalytic
quantities of fluoride, (ii) operate at room temperature, and (iii) provide
control over the pH of the reaction mixture.
This work was supported in part by DARPA, the Camille &
Henry Dreyfus Foundation, the Arnold and Mabel Beckman
Foundation, 3M, Mr. Louis Martarano, and The Pennsylvania
State University. We gratefully acknowledge the contributions of
Dr. Landy K. Blasdel in the preparation of this Article, Professor
Steven M. Weinreb for helpful suggestions, and Professor
Kenneth S. Feldman for the gifts of compounds 10, 12, and 14.
’ DEDICATION
†This Article is dedicated to Professor Steven M. Weinreb on the
occasion of his 70th birthday.
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