KHF2: A mild and selective desilylating agent for phenol tert-butyldimethylsilyl (TBDMS) ethers

Article abstract of DOI:10.1055/s-0036-1588350

TBDMS (t-BuMe₂Si, tert-butyldimethylsilyl) ethers of a variety of phenols have been deprotected with KHF₂ in MeOH, at room temperature. Carboxylic ester and labile phenolic acetate were unaffected under these conditions. In competition reactions between TBDMS ethers of a phenol and two primary benzylic alcohols, the phenolic ether underwent cleavage whereas the alcohol ethers remained intact. From a substrate containing both a phenolic hydroxyl group and a secondary, doubly benzylic hydroxyl group protected as TBDMS ethers, the phenol was rapidly and selectively released. Cleavage of TBDMS, TBDPS, and TIPS ethers of a phenol was also compared. TBDMS and TBDPS ethers underwent cleavage at room temperature within 30 minutes, whereas removal of the TIPS ether required 2.5 hours. Ease of cleavage appears to be TBDMS ≈ TBDPS > TIPS. At 60°C, TBDMS ethers of primary benzylic, allylic, and unactivated alcohols can be efficiently desilylated over a prolonged period (13-17 h). Thus, KHF₂ proves to be a mild and effective reagent for the selective desilylation of phenol TBDMS ethers at room temperature.

Full text of DOI:10.1055/s-0036-1588350

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
M. K. Lakshman et al.
Letter
Synlett
KHF2: A Mild and Selective Desilylating Agent for Phenol tert-
Butyldimethylsilyl (TBDMS) Ethers
Mahesh K. Lakshman*a,b
Fatou A. Tine◊a
Tashrique A. Khandaker◊a
Vikram Basava§a
Nana B. Agyemang§a
Michael S. A. Benavidez◊a
Marikone Gaši◊a
Lisa Guerrera◊a
Barbara Zajc*a,b
a Department of Chemistry and Biochemistry, The City Col-
lege of New York, 160 Convent Avenue, New York, NY
10031, USA
mlakshman@ccny.cuny
bzajc@ccny.cuny.edu
b The PhD Program in Chemistry, The City University of New
York, New York, NY 10016, USA
◊ Undergraduate research participants
§ Equal contributions from these authors
Received: 13.10.2016
Accepted after revision: 19.10.2016
Published online: 17.11.2016
TBDMS ≈ TBDPS > TIPS.2 Generally, phenol silyl ethers are
more rapidly cleaved under basic conditions as compared to
acidic conditions. For example, the half-life for the depro-
tection of the TBDMS ether of p-cresol is 3.5 minutes with
5% NaOH in 95% EtOH and ca. 4.5 hours with 1% HCl in 95%
EtOH.2 In a similar trend, half-lives for hydrolysis of the TIPS
and TBDPS ethers of p-cresol are >100 hours with 1% HCl in
95% EtOH.2 On the other hand, with 5% NaOH in 95% EtOH,
the half-lives for hydrolysis of these TIPS and TBDPS ethers
are ca. 3.1 hours and 6.5 minutes, respectively.2 The greater
lability of phenol silyl ethers to basic conditions is consis-
tent with both the greater electrophilicity of the silicon
center, due to delocalization of the oxygen atom lone pair,
as well as the fact that phenoxide is a good leaving group.
However, basic conditions can pose problems when base-
labile functionalities such as esters are present.
Fluoride ion is an exceptional agent for deprotection of
silyl ethers,3 and n-Bu4N+F–, NH4F, CsF, HF complexes such
as HF·pyridine, HF·Et3N, difluorosilicates such as tris(dime-
thylamino)sulfonium difluorotrimethylsilicate (TASF), and
tetrabutylammonium difluorotriphenylsilicate (TBAT) have
all found applications. Key to F-mediated desilylations is the
significantly stronger Si–F bond compared to the the Si–O
bond, and the formation of a fluorosiliconate intermediate.
Among the methods developed for cleavage of O-TBDMS
groups, there are generally fewer ones for accomplishing
desilylation of phenol TBDMS ethers. Some of these include
use of KF/18-Cr-6 in MeCN,4 KF-alumina in MeCN under ul-
trasound conditions,5 K2CO3 and Kryptofix 222,6
PdCl2(MeCN)2 in acetone at 75 °C,7 K2CO3 in wet EtOH at re-
flux,8 DMSO–H2O at 90 °C,9 NaOH/n-Bu4NHSO4 in 1,4-diox-
ane,10 LiOH in DMF,11 tetramethylguanidine in MeCN,12 KOH
DOI: 10.1055/s-0036-1588350; Art ID: st-2016-r0449-l
Abstract TBDMS (t-BuMe2Si, tert-butyldimethylsilyl) ethers of a vari-
ety of phenols have been deprotected with KHF2 in MeOH, at room
temperature. Carboxylic ester and labile phenolic acetate were unaf-
fected under these conditions. In competition reactions between
TBDMS ethers of a phenol and two primary benzylic alcohols, the phe-
nolic ether underwent cleavage whereas the alcohol ethers remained
intact. From a substrate containing both a phenolic hydroxyl group and
a secondary, doubly benzylic hydroxyl group protected as TBDMS
ethers, the phenol was rapidly and selectively released. Cleavage of
TBDMS, TBDPS, and TIPS ethers of a phenol was also compared. TBDMS
and TBDPS ethers underwent cleavage at room temperature within 30
minutes, whereas removal of the TIPS ether required 2.5 hours. Ease of
cleavage appears to be TBDMS ≈ TBDPS > TIPS. At 60 °C, TBDMS ethers
of primary benzylic, allylic, and unactivated alcohols can be efficiently
desilylated over a prolonged period (13–17 h). Thus, KHF2 proves to be
a mild and effective reagent for the selective desilylation of phenol
TBDMS ethers at room temperature.
Key words deprotection, desilylation, silicon, fluoride, potassium bi-
fluoride
Silyl ethers, a large class of hydroxyl protecting groups,
are a staple in contemporary organic synthesis.1 Among
these, the trimethylsilyl (TMS), triethylsilyl (TES), triisopro-
pylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), and tert-
butyldiphenylsilyl (TBDPS) are routinely employed. The rel-
ative rates of hydrolysis of O-silyl ethers in acidic and alka-
line media are different and can be exploited for selective
deprotection. For example, under acidic conditions, the
general order of hydrolytic lability is TMS > TES > TBDMS >
TIPS > TBDPS, and under basic conditions it is TMS > TES >
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
M. K. Lakshman et al.
Letter
Synlett
in EtOH,13 Cs2CO3 in wet DMF,14 SbCl5 in wet MeCN,15 DBU
in MeCN–H2O,16 LiOAc in DMF–H2O,17 KF in tetraethylene
glycol,18 Ce(SO4)2·4H2O in MeOH under microwave condi-
tions (130 °C) or conventional heating (60 °C),19 and NaH in
DMF.20 In the context of deprotecting alkyl silyl ethers in
the presence of phenolic silyl ethers, catalytic AlCl3·6H2O in
MeOH or i-PrOH has been investigated for removal of phe-
nolic TBDMS groups.21 Catalytic NaAuCl4·2H2O in MeOH has
been used to deprotect four phenolic TBDMS groups, but
the method gave a low yield with an electron-deficient phe-
nol.22
KHF2
MeOH
r.t.
OTBDMS
OH
R
R
OH
Me
OH
OH
OH
Ac
N
NC
2: 1 h, 88%
Br
1: 0.5 h, 87%
OHC
OMe
H
3: 2 h, 95%
4: 1.5 h, 75%
N
OH
OH
OH
OH
Me
In connection with ongoing work on desilylations of
some nucleoside substrates, we found the compounds to be
exceptionally sensitive to a variety of conventional fluoride
reagents. This necessitated the evaluation of alternate re-
agents and we have found that KHF2 in MeOH is a mild re-
agent for cleavage of phenolic TBDMS groups. A major con-
sideration in the use of silyl protecting groups for hydroxyl
functionalities is the selective cleavage of one silyl ether
over others, and particularly when different hydroxyl
groups bear an identical silyl protection.23–25 Thus, we also
wanted to ascertain the selectivity of KHF2 for removal of a
phenolic TBDMS protection over comparable protection of
1° and 2° alkanols, and evaluate removal of a phenolic
TBDMS group in the presence of a carboxylic ester and a
phenolic acetate. Related to this work, a single report exists
wherein a fluoride buffer prepared from 0.1 M HF and 0.1
M NaF was used to desilylate a relatively sensitive phenolic
TBDMS ether.26
Several phenol TBDMS ethers were synthesized and
subjected to desilylation with KHF2 in MeOH at room tem-
perature. Although in initial assessments with (4-bro-
mophenoxy)(tert-butyl)dimethylsilane, 1.5 equivalents of
KHF2 gave a high 91% yield of 1 in 0.5 hours, 2.5 equivalents
were used to ensure rapid and complete cleavage in all cas-
es. Scheme 1 shows products, reaction times, and yields ob-
tained. All reactions, with the exception of one (see below),
proceeded efficiently at room temperature.
MeO2C
HO
8: 1 h, 67%
5: 2 h, 89%
6: 1 h, 90%
7: 2 h, 71%
at 50 °C
HO
OH
HO
OH
10: 2 h, 84%
9: 48 h, 79%
Scheme 1 Results from the deprotection of several phenol TBDMS
ethers
Next, we investigated the suitability of the reaction con-
ditions for removal of a phenolic TBDMS group, in the pres-
ence of a phenolic acetate. For this, hydroquinone (8) was
converted
into
4-[(tert-butyldimethylsilyl)oxy]phenol
(11)27 by monosilylation using excess hydroquinone. Com-
pound 11 upon acetylation gave 4-[(tert-butyldimethylsi-
lyl)oxy]phenyl acetate (12).28 Exposure of this differentially
diprotected hydroquinone 12 to the desilylation conditions
gave hydroquinone monoacetate 1329 in an excellent 97%
yield (Scheme 2). This clearly showed that highly labile
phenolic acetate is stable under the reaction conditions.
TBDMSCl
imidazole
DMF
OH
OTBDMS
HO
HO
8
11
A methyl ester was unaffected in product 6. Deprotec-
tion of the sterically congested TBDMS ether of 2,6-dimeth-
ylphenol required heating at 50 °C, but this reaction was
complete within two hours. Bis-TBDMS ethers were also
evaluated. Hydroquinone bis-TBDMS ether was cleaved
readily to yield hydroquinone (8) within one hour. In con-
trast, the bis-TBDMS ether of 1,1′-bi-(2-naphthol) required
a long reaction time at room temperature, nevertheless, a
good yield of product 9 was obtained. The reaction time for
the 1,1′-binaphthol derivative appears to be unique to this
system because, just as with the bis-TBDMS derivative of
hydroquinone, bisphenol F (10) could be obtained by cleav-
age of the corresponding bis-TBDMS ether within two
hours.
Ac2O
DMAP
CH2Cl2
KHF2
MeOH
r.t.
OH
OTBDMS
97%
AcO
AcO
13
12
Scheme 2 Synthesis and desilylation of the monoacetoxy mono-
TBDMS ether of hydroquinone to yield 4-hydroxyphenyl acetate
Competitive desilylation of TBDMS ethers of a phenol
and two benzylic alcohols was then evaluated. First, an
equimolar mixture of (4-bromophenoxy)(tert-butyl)di-
methylsilane (14) and tert-butyl[(2,3-dimethoxyben-
zyl)oxy]dimethylsilane (15) was exposed to the desilylation
conditions for 30 minutes. In this period, only compound
14 underwent complete desilylation, and this situation re-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
M. K. Lakshman et al.
Letter
Synlett
mained unaltered even after one hour (Scheme 3). From
this reaction 4-bromophenol (1) was isolated in 91% yield,
and 97% of unreacted 15 was reisolated.
ary alcohol, within a single molecule (Scheme 4). For this,
benzhydrol 17 was synthesized by lithiation of TBDMS-pro-
tected p-bromophenol (14) and reaction with 2,3-dime-
thoxybenzaldehyde. The secondary alcohol was silylated to
yield compound 18, which upon exposure to the desilyla-
tion conditions gave phenol 19 in an excellent 96% yield.
Using silyl ethers of p-bromophenol, the ability to
cleave tert-butyldiphenylsilyl (TBDPS) and triisopropylsilyl
(TIPS) ethers with KHF2/MeOH, and in comparison to the
corresponding TBDMS derivative, was evaluated. Three re-
actions were conducted, one with each of the silyl ethers,
and were stopped after 30 minutes. The mixtures were
chromatographed, and the data from these experiments are
shown in Table 1.
OTBDMS
OH
KHF2
MeOH
r.t.
Br
Br
14
1 (91%)
OTBDMS
OTBDMS
OMe
OMe
OMe
OMe
15
15 (97%)
OTBDMS
OH
KHF2
MeOH
r.t.
Br
Br
Br
Br
14
16
1 (87%)
Table 1 Comparison of the Deprotection of TBDMS, TBDPS, and TIPS
Ethers of p-Bromophenola
OTBDMS
OTBDMS
KHF2
16 (91%)
MeOH
r.t., 0.5 h
OPG
OH
Scheme 3 Competitive deprotection of TBDMS ethers of a phenol and
two benzylic alcohols
Br
Br
14, 20, 21
1
Competitive desilylation was also evaluated with (4-
bromophenoxy)(tert-butyl)dimethylsilane (14) and [(4-
bromobenzyl)oxy](tert-butyl)dimethylsilane (16), both
containing a comparable bromine substituent (Scheme 3).
As in the previous example, after 30 minutes and one hour
of reaction, only the phenolic silyl group had undergone
cleavage. From this reaction, 87% yield p-bromophenol (1)
was obtained, and 91% of unreacted 16 was reisolated.
These experiments clearly indicated high selectivity for
phenolic TBDMS cleavage in the presence of a comparable
benzylic ether.
Substrate
PG
Yield of 1 (%)
SMb recovered (%)
14
20
21
t-BuMe2Si
t-BuPh2Si
(i-Pr)3Si
95
92
25
none
none
65
a Yields reported are of isolated materials obtained by chromatography.
b SM = starting material.
Data in Table 1 show that both TBDMS and TBDPS
groups undergo complete cleavage within 30 minutes, but
that deprotection of the TIPS group is significantly slower.
However, within 2.5 hours the TIPS group was fully re-
moved with an ensuing p-bromophenol yield of 92% (with
silyl ether 21). A separate competitive desilylation reaction
of silyl ethers 14 and 20 gave a 95% yield of p-bromophenol
(1). These collective results indicate that TBDMS and TBDPS
groups are removed with similar ease. Thus, order of re-
moval of the three silyl groups is TBDMS ≈ TBDPS > TIPS.
Whereas this order is similar to that for removal of these
groups under basic conditions,2 it is notable that phenolic
acetate and ester groups are unaffected.
We then evaluated the utility of KHF2/MeOH for cleav-
age of alkanol TBDMS ethers. It was discovered that second-
ary alcohol TBDMS ethers were recalcitrant to cleavage,
even at 60 °C. However, at 60 °C, TBDMS ethers of primary
benzylic, an allylic, and an unactivated alcohol underwent
desilylation reasonably efficiently (Scheme 5), but clearly
slower than deprotection of phenolic TBDMS ethers.
The next evaluation was the selective release of a phe-
nolic hydroxyl group from a compound that contained
TBDMS ethers of the phenol and a doubly benzylic second-
OTBDMS
OTBDMS
HO
n-BuLi, Et2O, 0 °C to r.t.
then cool to 0 °C
add 2,3-dimethoxy-
benzaldehyde, r.t.
67%
MeO
MeO
Br
14
17
TBDMSCl
imidazole
DMF
96%
KHF2
MeOH
r.t.
OTBDMS
OH
TBDMSO
MeO
TBDMSO
96%
MeO
MeO
MeO
In summary, phenolic TBDMS groups are readily depro-
tected by KHF2 in MeOH at room temperature.30 With ap-
propriate handling care,30,31 this solid reagent is convenient
to use and is highly selective for desilylation of phenolic
18
19
Scheme 4 Selective deprotection of a phenolic TBDMS ether in the
presence of a TBDMS ether of a secondary, doubly benzylic alcohol
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
M. K. Lakshman et al.
Letter
Synlett
(10) NaOH/n-Bu4NHSO4: Crouch, R. D.; Stieff, M.; Frie, J. L.;
Cadwallader, A. B.; Bevis, D. C. Tetrahedron Lett. 1999, 40, 3133;
a methyl ester and benzylic acetate do not survive the reaction
conditions.
(11) LiOH/DMF: Ankala, S. V.; Fenteany, G. Tetrahedron Lett. 2002,
43, 4729.
(12) TMG in MeCN: Oyama, K.-i.; Kondo, T. Org. Lett. 2003, 5, 209;
under the conditions a phenolic TBDMS ether is selectively
cleaved over a primary TBDMS ether, but phenolic acetates are
cleaved.
(13) KOH/EtOH: Jiang, Z.-Y.; Wang, Y.-G. Chem. Lett. 2003, 32, 568.
(14) Cs2CO3 in wet DMF: Jiang, Z.-Y.; Wang, Y.-G. Tetrahedron Lett.
2003, 44, 3859; under the conditions phenol TBDMS ethers are
cleaved at r.t. and benzylic TBDMS ethers are cleaved at 100 °C,
but other alkyl TBDMS ethers do not react.
(15) SbCl5: Glória, P. M. C.; Prabhakar, S.; Lobo, A. M.; Gomes, M. J. S.
Tetrahedron Lett. 2003, 44, 8819; alkyl TBDMS ethers are also
cleaved under the conditions.
(16) DBU/MeCN–H2O: Yeom, C.-E.; Kim, H.-W.; Lee, S. Y.; Kim, B. M.
Synlett 2007, 146; selective removal of phenolic TBDMS groups
occurs in preference to primary alcohol TBDMS ethers, and
methyl ester as well as alkyl acetate are stable.
KHF2
MeOH
60 °C
R
OTBDMS
OH
R
OH
OH
S
N
OH
OMe
OH
Br
Me
OMe
22: 15 h, 85%
23: 16 h, 94%
24: 13 h, 75%
25: 17 h, 75%
Scheme 5 Deprotection of TBDMS ethers of two benzylic, an allylic,
and an unactivated alcohol
TBDMS groups in the presence of comparable silyl ethers of
primary and secondary alcohols. Carboxylic esters and the
relatively labile phenolic acetate are stable under the desil-
ylation conditions. TIPS and TBDPS ethers of p-bromophe-
nol are also cleaved at room temperature and the ease of
deprotection is TBDMS ≈ TBDPS > TIPS. Although this paral-
lels the order for basic cleavage,2 ester and phenolic acetate
remain unaffected. At elevated temperature (60 °C), KHF2
does cause deprotection of benzylic, allylic, and unactivated
primary alcohol TBDMS ethers, albeit quite slowly. Also no-
tably, KHF2 (>99%) costs ~$17/mol and is cheaper than KF
(>99%) that costs ~$23/mol.32 Thus, KHF2 should find broad
applications in the desilylations of a range of phenolic
TBDMS compounds,30 even in the presence of primary and
secondary alcohols protected with the same silyl group.
(17) LiOAc: Wang, B.; Sun, H.-X.; Sun, Z.-H. J. Org. Chem. 2009, 74,
1781.
(18) (a) KF/tetraethylene glycol: Yan, H.; Oh, J.-S.; Song, C.-E. Org.
Biomol. Chem. 2011, 9, 8119. (b) Phenolic TES, TIPS, TBDMS,
TBDPS ethers are cleaved at room temperature in 15–30 min.
TES ethers of 1°, 2°, and 3° alcohols are also cleaved at r.t. A
primary alcohol TBDMS ether was cleaved at 70–80 °C. TIPS,
TBDMS, and TBDPS ethers of benzyl alcohol underwent depro-
tection at 80 °C in 1.5 h, 3.5 h, and 5 h, respectively. A phenolic
acetate was stable to the phenolic TES ether deprotection..
(19) CeSO4: González-Calderón, D.; González-González, C. A.;
Fuentes-Benítez, A.; Cuevas-Yáñez, E.; Corona-Becerril, D.;
González-Romero, C. Helv. Chim. Acta 2014, 97, 965.
(20) NaH/DMF:Fernandes, R. A.; Gholap, S. P.; Mulay, S. V. RSC Adv.
2014, 4, 16438; a phenolic acetate was stable to the conditions.
(21) González-Calderón, D.; Benitez-Puebla, L. J.; Gonzalez-Gonza-
lez, C. A.; Garcia-Eleno, M. A.; Fuentes-Benitez, A.; Cuevas-
Yañez, E.; Corona-Becerril, D.; González-Romero, C. Synth.
Commun. 2014, 44, 1258.
Acknowledgment
This work was supported by NSF Grants CHE-1265687 to MKL and
CHE-1565754 to BZ. Infrastructural support at CCNY was provided by
NIH grant G12MD007603 from the National Institute on Minority
Health and Health Disparities. We thank Dr. Lijia Yang for some HRMS
data.
Supporting Information
(22) Zhang, Q.; Kang, X.; Long, L.; Zhu, L.; Chai, Y. Synthesis 2015, 47,
55.
(23) Collington, E. W.; Finch, H.; Smith, I. J. Tetrahedron Lett. 1985,
26, 681.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588350.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(24) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031.
(25) Crouch, R. D. Tetrahedron 2013, 69, 2383.
(26) Kendall, P. M.; Johnson, J. V.; Cook, C. E. J. Org. Chem. 1979, 44,
1421.
References and Notes
(1) Greene’s Protective Groups in Organic Synthesis, 4th ed.; Wuts, P.
G. M.; Greene, T. W., Eds.; John Wiley and Sons: Hoboken, 2007.
(2) Kocieński, P. J. Protecting Groups; Thieme: Stuttgart, 2005, 3rd
ed..
(3) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
(4) KF/18-Cr-6: Just, G.; Zamboni, R. Can. J. Chem. 1978, 56, 2725.
(5) KF/alumina: Schmittling, E. A.; Sawyer, J. S. Tetrahedron Lett.
1991, 32, 7207.
(6) K2CO3/Kriptofix 222: Prakash, C.; Saleh, S.; Blair, I. A. Tetrahe-
dron Lett. 1994, 35, 7565.
(7) PdCl2: Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1996, 37, 153.
(8) K2CO3 in EtOH: Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1997,
38, 187.
(27) (a) Stern, A.; Swenton, J. S. J. Org. Chem. 1987, 52, 2763.
(b) McKerlie, F.; Rudkin, I. M.; Wynne, G.; Procter, D. J. Org.
Biomol. Chem. 2005, 3, 2805. (c) Kahl, P.; Tkachenko, B. A.;
Novikovsky, A. A.; Becker, J.; Dahl, J. E. P.; Carlson, R. M. K.;
Fokin, A. A.; Schreiner, P. R. Synthesis 2014, 46, 787.
(28) (a) It appears that synthesis and spectral data for 4-
(MeCO)C6H4OTBDMS have been erroneously ascribed as that of
compound 12: Xu, Z.-Y.; Xu, D.-Q.; Liu, B.-Y.; Luo, S.-P. Synth.
Commun. 2003, 33, 4143; see Table 2, 3j. (b) Baldwin, N. J.; Nord,
A. N.; O’Donnell, B. D.; Mohan, R. S. Tetrahedron Lett. 2012, 53,
6946; reports a synthesis of compound 12 – a listing of spectral
data is not provided, and the product is referenced to the Synth.
Commun. paper cited in ref. 28a.
(9) DMSO/H2O: Maiti, G.; Roy, S. C. Tetrahedron Lett. 1997, 38, 495;
this method deprotects aryl, benzyl, and allyl TBDMS ethers.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

E
M. K. Lakshman et al.
Letter
Synlett
(29) (a) Coombes, C. L.; Moody, C. J. J. Org. Chem. 2008, 73, 6758.
(b) Cepanec, I.; Litvić, M. ARKIVOC 2008, (ii), 19. (c) Chen, H.; Li,
X.-H.; Gong, J.; Song, H.; Liu, X.-Y.; Qin, Y. Tetrahedron 2016, 72,
347.
(30) Caution! KHF2 can produce HF upon contact with water and
MeOH. It has been shown to etch glass in repeated use of glass-
ware for the synthesis of organotrifluoroborates.31
reduced pressure and loaded onto a silica column (100–200
mesh) packed with hexanes (adequate caution was exercised to
ensure complete transfer of the crude material). Elution with
hexanes, followed by 30% EtOAc in hexanes gave 0.148 g (97%
yield) of 4-hydroxyphenyl acetate (13) as a white powder. Rf =
0.37 (40% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3): δ =
6.95 (d, J = 8.8 Hz, 2 H, ArH), 6.81 (d, J = 8.8 Hz, 2 H, ArH), 4.69
(br s, 1 H, OH), 2.28 (s, 3 H, CH3). 13C NMR (125 MHz, CDCl3): δ =
170.4, 153.7, 144.5, 122.6, 116.3, 21.2. ESI-HRMS (TOF): m/z
calcd for C8H8O3Na [M + Na]+: 175.0366; found: 175.0380.
(31) Lennox, A. J. J. PhD Dissertation: Organotrifluoroborate prepara-
tion, coupling and hydrolysis; University of Bristol: UK, 2013.
(32) Comparison based upon catalogue prices of a leading chemicals
supplier.
Representative Procedure for Desilylation of Phenol TBDMS
Ethers: 4-Hydroxyphenyl Acetate (13)29
In an oven-dried 25 mL round-bottom flask, a mixture of silyl
ether 12 (0.266 g, 1 mmol) and KHF2 (0.195 g, 2.5 mmol) in
anhydrous MeOH (10.0 mL) was stirred at r.t. The reaction was
monitored by TLC using 40% EtOAc in hexanes and was found to
be complete within 1 h. The mixture was evaporated under
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E