DBU-mediated mild and chemoselective deprotection of aryl silyl ethers and tandem biaryl ether formation

Article abstract of DOI:10.1055/s-2006-958425

An efficient method for the selective cleavage of aryl silyl ethers is established using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). With either 1.0 or 0.10 equivalent of DBU, smooth desilylation of various aryl silyl ethers was accomplished selectively in the presence of alkyl silyl ethers and other base-sensitive groups such as acetate and ester. In addition, direct transformation of aryl silyl ethers into biaryl ethers using a catalytic amount of DBU was possible through tandem desilylation and S_NAr reaction with activated aryl fluorides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958425

146
LETTER
DBU-Mediated Mild and Chemoselective Deprotection of Aryl Silyl Ethers
and Tandem Biaryl Ether Formation
D
BU-Mediated D
h
eprotection
a
of
A
ryl Sily
n
l
Ethers
a
nd
g
T
andem
E
th
-
erificati
E
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Korea
Fax +82(2)8727505; E-mail: kimbm@snu.ac.kr
Received 21 September 2006
N
Abstract: An efficient method for the selective cleavage of aryl
silyl ethers is established using 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU). With either 1.0 or 0.10 equivalent of DBU, smooth de-
silylation of various aryl silyl ethers was accomplished selectively
in the presence of alkyl silyl ethers and other base-sensitive groups
such as acetate and ester. In addition, direct transformation of aryl
silyl ethers into biaryl ethers using a catalytic amount of DBU was
possible through tandem desilylation and SNAr reaction with
activated aryl fluorides.
N
DBU (1 equiv)
OTBDMS
OH
MeCN–H2O (95:5)
r.t., 20 min
98%
Equation 1
Key words: chemoselective, catalytic, desilylation, DBU, biaryl
ether
First we examined a variety of Lewis bases in methanolic
acetonitrile to evaluate their desilylating ability on aryl
silyl ethers (Table 1). Strong amine bases such as 4-
(N,N-dimethylamino)pyridine (DMAP), 1,4-diazabicyc-
lo[2.2.2]octane (DABCO), N-methylmorpholine (NMM),
and proton sponge were totally inactive. Only TMG
provided 2-naphthol in a low yield (31%). However, when
DBU was employed, desilylation proceeded smoothly
within one hour, giving a nearly quantitative yield of the
product (96%). From this study, it became clear that DBU
has outstanding desilylating ability unlike other Lewis
bases.9
Silyl ethers have been utilized as one of the most popular
protecting groups of the hydroxyl functionality.1 Many
synthetic targets for biological application are equipped
with multiple hydroxyl groups and a number of protocols
on chemoselective desilylation of bissilyl ethers have
been developed.2,3 Nevertheless, reports on the chemo-
selective cleavage of aryl silyl ethers are relatively rare in
comparison with alkyl silyl ethers. Though tetrabutylam-
monium fluoride (TBAF) is widely used for desilylation,
it seldom differentiates various silyl ethers.4 Most proto-
cols on chemoselective cleavage of aryl silyl ethers are
based upon the utilization of alkali metal hydroxides and
carbonates.5 However, they require either excess reagents,
harsh reaction conditions, or sometimes both, to yield
reasonable outcome. Furthermore, these methods are
often incompatible with hydroxide-sensitive functional
groups such as esters.5d Recently, Kondo’s group reported
a novel protocol for the selective cleavage of aryl silyl
ethers using 1,1,3,3-tetramethylguanidine (TMG).6
Though this particular amine base proved to be effective
for desilylation of aryl silyl ethers, use of excess reagents
at elevated temperature was required for satisfactory
results. While we were searching for milder methods to
deprotect aryl silyl ethers chemoselectively, we en-
countered interesting desilylating activity of DBU7
(Equation 1). This paper reports on the chemoselective
desilylation using a catalytic amount of DBU, and a
tandem reaction based upon the intermediate aryl oxide
formation during the deprotection as a part of our ongoing
research on protecting group chemistry.8
Table 1 Desilylation of 2-Naphthyl tert-Butyldimethylsilyl Ether
Using Various Lewis Bases
OTBDMS
OH
Lewis base (1 equiv)
MeCN–MeOH (95:5)
r.t., 1 h
Entry
Lewis base
Yield (%)a
1
2
3
DBU
TMG
96
31
0
DABCO, NMM,
DMAP, proton sponge
a Yield of isolated 2-naphthol.
We then examined the effect of various solvents and,
again, the desilylation of 2-naphthyl tert-butyldimethyl-
silyl ether was chosen as a model reaction (Table 2). First
of all, reactions in nonpolar solvents such as dichloro-
methane or toluene were totally inert (entry 1). Use of a
polar solvent without any proton source such as aceto-
nitrile, tetrahydrofuran and dimethyl sulfoxide exhibited
some reactivity affording 13%, 14%, and 15% yields of
the product, respectively (entries 2–4). When methanol
SYNLETT 2007, No. 1, pp 0146–0150
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-958425; Art ID: U11206ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
DBU-Mediated Deprotection of Aryl Silyl Ethers and Tandem Etherification
147
was employed, desilylation underwent smoothly within
one hour, though the reaction did not reach completion
(entry 5). When we added a small portion of a protic
solvent such as methanol to acetonitrile, the reaction went
almost to completion (entry 6). Moreover, a noticeable in-
crease in the reaction rate was observed when the protic
additive was switched from methanol to water, and a near-
ly quantitative (98%) yield of the product was obtained in
just 20 minutes (entry 7). It was confirmed through vary-
ing amounts of water that only 1.5 equivalents of water
was enough to furnish the same results. Reaction in
aqueous tetrahydrofuran also afforded comparable but
slightly inferior result to that in acetonitrile (entry 8). Con-
sequently, aqueous acetonitrile was chosen as an optimal
reaction medium. Since the role of DBU can be essentially
catalytic, reaction with only a catalytic amount of DBU
was tested and the desilylation proceeded smoothly with
only 0.1 equiv of DBU upon heating at 60 °C for four
hours (entry 9).
Table 2 Desilylation of 2-Naphthyl tert-Butyldimethylsilyl Ether
with DBU (1 equiv) in Various Solvents
OTBDMS
OH
DBU (1 equiv)
solvent, r.t., 1 h
Entry
Solvent
Yield (%)a
1
2
3
4
5
6
7b
8
9
CH2Cl2 or toluene
MeCN
0
13
THF
14
DMSO
15
MeOH
80
MeCN–MeOH = 19:1
MeCN–H2O = 19:1
THF–H2O = 19:1
MeCN–H2O = 19:1
96 (31)c
98 (58)c
89
95d
Results from the cleavage of various aryl silyl ethers using
DBU in aqueous acetonitrile are summarized in Table 3.
With one equivalent of DBU, all the silyl groups were re-
moved smoothly irrespective of the substitution patterns
on the silicon (entries 1–4) or the aromatic ring (entries 5–
8), and 0.1 equivalent of DBU was sufficient to drive the
a Yields of isolated products.
b Reaction was carried out for 20 min.
c Numbers in parentheses are the results employing TMG (1 equiv).
d Reaction was carried out with DBU (0.1 equiv) at 60 °C for 4 h.
Table 3 Deprotection of Various Aryl Silyl Ethers Using DBU in Aqueous Acetonitrilea
DBU (1 equiv)
OH
OSiR3
R'
R'
MeCN–H2O (95:5)
r.t.
Entry
1
Silyl ether
Phenol
Time
Yield (%)b
OTES
OH
<5 min
(1 h)
98
(95)c
2
3
4
5
20 min
(4 h)
98
(95)
OTBDMS
OTBDPS
OTIPS
OH
OH
OH
OH
15 min
(1.5 h)
98
(95)
2 h
97
95
<5 min
OTBDMS
O2N
O2N
6
7
10 min
(1 h)
99
(98)
OTBDMS
OH
MeO2C
MeO
MeO2C
MeO
3.5 h
95
OTBDMS
OH
a Reaction conditions: A mixture of arylsilyl ether and 1 equiv DBU was stirred at r.t. for a given time. Values in parentheses are the times and
yields for the reaction with DBU (0.1 equiv) at 60 °C.
b Yields of isolated products.
c This particular catalytic reaction was carried out at r.t.
Synlett 2007, No. 1, 146–150 © Thieme Stuttgart · New York

148
C.-E. Yeom et al.
LETTER
desilylation albeit at higher temperature (60 °C) and with media, and the reverse is true under acidic and neutral
longer reaction time in most cases (entries 2, 3, and 6). In conditions.2,3,6,8a In our case, the silyl ethers of aryl alco-
the case of triethylsilyl ether, even the catalytic reaction hols were also removed selectively leaving aliphatic silyl
took one hour at room temperature to give 95% yield ethers intact. Reactions of compounds not only with di-
(entry 1). It is of particular note that methyl ester, which TBDMS (entries 2, 5, 6, and 7) but also diTES (entry 1),
shows low compatibility in hydroxide-mediated desilyla- diTIPS (entry 3), and diTBDPS ethers (entry 4 and 8)
tion,5d survived this condition. Several factors that deter- showed excellent chemoselectivities, providing high
mined the desilylation rate were identified. First, among yields of the monodesilylated aryl alcohols. Moreover,
trialkylsilyl groups, the reactivity was found to be in the employment of the catalytic system also gave the corre-
order of triethylsilyl (TES) > tert-butyldiphenylsilyl sponding aryl alcohols in high yields (entries 1, 2 and
(TBDPS) ≈ tert-butyldimethylsilyl (TBDMS) > triiso- 6–9). A notable example is the selective cleavage of
propylsilyl (TIPS), which is consistent with the steric re- TBDMS group in the presence of an acetate group, a
quirement.10 The electronic nature of the aromatic ring highly labile group in a basic environment (entry 9).
substituents was also found to influence the desilylation When this substrate was exposed to hydroxide-promoted
rate. Silyl ethers with electron-withdrawing substituents desilylating conditions with one equivalent of tetrabutyl-
were cleaved more readily than those with electron-donat- ammonium hydroxide (TBAOH), the desired product was
ing groups (entries 5–7).8a
isolated in only 74% yield, yielding a significant amount
(22%) of diol as a by-product.
Next, chemoselective desilylation of bissilyl ethers of aryl
and aliphatic alcohols was examined (Table 4). It has al- Since DBU has been commonly employed as a base, we
ready been described that the cleavage of aryl silyl ethers envisioned that the basic nature of DBU can be utilized,
is generally faster than that of alkyl silyl ethers in basic for example, in connection with SNAr reaction. SNAr
Table 4 Chemoselective Deprotection of Aryl Silyl Ethers to Aryl Alcohols Using DBU in Aqueous Acetonitrile
OSiR3
DBU
OSiR3
n
R3SiO
n
HO
MeCN–H2O (95:5)
r.t.
R = ethyl, tert-butyldimethyl,
triisopropyl, tert-butyldiphenyl
n = 0, 1
OTES
Entry
1
Silyl ether
Phenol
DBU (equiv) Temp (°C) Time
Yield (%)a
OTES
1.0
0.1
25
25
10 min
1.5 h
93
96
HO
TESO
2
3
4
5
1.0
0.1
25
60
1 h
5 h
95
98
OTBDMS
OTBDMS
OTIPS
TBDMSO
TIPSO
HO
HO
HO
1.0
1.0
1.0
60
25
25
3 h
94
99
94
OTIPS
1.5 h
1.5 h
OTBDPS
OTBDPS
TBDPSO
OTBDMS
OTBDMS
OH
OTBDMS
6
1.0
0.1
25
60
1.5 h
7 h
99
98
OTBDMS
OTBDMS
HO
TBDMSO
7
8
9
1.0
0.1
25
60
2.5 h
7 h
94
97
OTBDMS
OTBDMS
TBDMSO
TBDPSO
TBDMSO
HO
HO
HO
1.0
0.1
25
60
1.5 h
5 h
94
90
OTBDPS
OAc
OTBDPS
OAc
1.0
0.1
25
60
1.5 h
7 h
95
95
a Yield of isolated product.
Synlett 2007, No. 1, 146–150 © Thieme Stuttgart · New York

LETTER
DBU-Mediated Deprotection of Aryl Silyl Ethers and Tandem Etherification
149
reaction has received significant attention since biaryl activated aryl fluorides. In the course of SNAr reaction, a
ether motifs are the core constituents of many biologically fluoride anion will be generated as a leaving group, which
active compounds11 and thermoplastic polymers.12 In this will then facilitate further TBDMS cleavage, thus acceler-
regard, we examined DBU in the context of tandem de- ating the process. It would therefore be possible to accom-
silylation and biaryl ether formation based on the premise plish tandem desilylation and SNAr reaction with only a
that the reaction of aryl silyl ethers with DBU generates an catalytic amount of DBU and water (Table 5).
aryloxy anion, which can be utilized for the SNAr with
Table 5 Transformation of Aryl TBDMS Ether into Biaryl Ether through Tandem Desilylation and SNAr with a Catalytic Amount of DBU
DBU
(0.12 equiv)
OTBDMS
F
O
+
R
R'
R
R'
DMSO, H2O
(0.18 equiv)
80 °C
1.2 equiv
1 equiv
Entry
1
Aryl fluoridea
Silyl ether
Biaryl ether
Yield (%)b
88c
OTBDMS
I
NO2
O
O
MeO
MeO
NO2
OMe
2
3
III
91d
OTBDMS
NO2
OMe
I
88e
NO2
OTBDMS
OTBDMS
O
NO2
4
5
II
II
86f
89f
NO2
O
OTBDMS
NO2
O
Cl
Cl
6
III
88f
O
OTBDMS
Cl
NO2
Cl
a Aryl fluoride: I: 2,4-dinitrofluorobenzene, II:1-fluoro-2-nitrobenzene, III: 1-fluoro-4-nitrobenzene.
b Yields of isolated products.
c Reaction time: 30 min.
d Reaction time: 1.5 h.
e Reaction time: 1 h.
f Reaction time: 2 h.
Synlett 2007, No. 1, 146–150 © Thieme Stuttgart · New York

150
C.-E. Yeom et al.
LETTER
M.; Frie, J. L.; Cadwallader, A. B.; Bevis, D. C. Tetrahedron
Lett. 1999, 40, 3133. (e) Wilson, N. S.; Keay, B. A.
Tetrahedron Lett. 1997, 38, 187.
Through several modifications, we were pleased to find
the optimal reaction conditions for the tandem reactions.
Three essential factors were identified for the successful
aryl ether formation, namely, dimethyl sulfoxide, DBU
and water. In the absence of DBU, reactions did not pro-
ceed at all. When anhydrous dimethyl sulfoxide or other
aprotic solvents alone were employed, the overall reaction
was seriously retarded. Finally, running the reaction in
DMSO with a small amount of water at elevated temper-
ature accomplished the successful tandem reaction. Sev-
eral electronically divergent aryl TBDMS ethers and aryl
fluorides were coupled to biaryl ethers in dimethyl sulfox-
ide with the use of only 0.12 equivalent of DBU and 0.18
equivalent of water as outlined in Table 4. Both dinitro-
(entries 1) and mononitro-substituted aryl fluorides (en-
tries 2–5) were coupled with the in situ generated phenox-
ides.13 Unfortunately, when bissilyl ethers possessing
both alkyl and aryl silyl ethers were subjected to this tan-
dem reaction conditions, the result was quite complex,
presumably due to nonselective deprotection of both silyl
ethers aroused by free fluorides.
(6) Oyama, K.-I.; Kondo, T. Org. Lett. 2003, 5, 209.
(7) (a) Oediger, H.; Möller, F.; Eiter, K. Synthesis 1972, 591.
(b) Hermecz, I. Advances in Heterocyclic Chemistry;
Katrizky, A. R., Ed.; Academic Press Inc.: New York, 1987,
Chap. 42, 83.
(8) (a) Yeom, C.-E.; Kim, Y. J.; Lee, S. Y.; Shin, Y. J.; Kim, B.
M. Tetrahedron 2005, 61, 12227. (b) Yeom, C.-E.; Lee, S.
Y.; Kim, Y. J.; Kim, B. M. Synlett 2005, 1527.
(9) Known pKa(DMSO) values of the protonated Lewis bases:
DABCO: 8.93, proton sponge: 7.50, TMG: 13.6, DBU: 12.0
(estimated value). For details, see: (a) Bordwell pKa Table
(acidity in DMSO): http://chem.wisc.edu/areas/reich/
pkatable (accessed July 2006). (b) David Evans research
group: http://daecr1.harvard.edu/pKa/pka.html (accessed
July 2006).
(10) This trend corresponds to the report on the susceptibility of
silylated cresols to basic hydrolysis, which was examined
using 5% NaOH in 95% MeOH: Davies, J. S.;
Higginbotham, C. L.; Tremeer, E. J.; Brown, C.; Treadgold,
R. C. J. Chem. Soc., Perkin. Trans. 1 1992, 3043.
(11) (a) Rao, A. V.; Gurjar, M. K.; Reddy, K. L.; Rao, A. S.
Chem. Rev. 1995, 92, 2135. (b) Nicolaou, K. C.; Boddy, C.
N. C. J. Am. Chem. Soc. 2002, 124, 10451.
(12) Cotter, R. J. Engineering Plastics: A Handbook of Polyaryl
Ethers; Gordon and Breach: Langhorne, PA, 1995.
(13) The nitro-substituted aryl fluorides were chosen as
representative substrates, and we found that aromatic
fluorides substituted with other electron-withdrawing
groups, such as cyano or formyl, were also effective. The
results will be described in a full account.
(14) Cleavage of Aryl Silyl Ethers (Table 3, Entry 2); Typical
Procedure: To a magnetically stirred solution of tert-
butyldimethyl(2-naphthalenyloxy)silane (460 mg, 1.78
mmol) in anhyd MeCN (3.4 mL) and H2O (0.18 mL) was
added DBU (0.26 mL, 1.78 mmol). After the starting
material disappeared (TLC), sat. aq NH4Cl solution (5 mL)
was poured into the reaction mixture. The mixture was
extracted with CH2Cl2 (2 ꢀ 5 mL), and the organic layer was
collected, dried over MgSO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified
further by passing through a short silica gel column (ca 5 cm)
and after vacuum evaporation pure 2-naphthol was obtained
(250 mg, 98% yield). Desilylated position of bissilyl ether
was determined by the chemical shift difference of the free
alcohol or alkyl substituents on silicon in NMR. Generally,
the chemical shifts of aryl alcohols are higher than those of
the aliphatic alcohols and alkyl substituent of aryl silyl ethers
also exhibited more downfield signals in 1H and 13C NMR
than those of aliphatic ones.
(15) Tandem, One-Pot Biaryl Ether Formation (Table 5,
Entry 2); Typical Procedure: To a magnetically stirred
solution of tert-butyldimethyl-(4-methoxyphenoxy)silane
(410 mg, 1.73 mmol) in anhyd DMSO (3.5 mL) and H2O (4
mL) were added p-fluoronitrobenzene (152 mL, 1.44 mmol),
and DBU (13 mL, 0.173 mmol) sequentially at r.t. The
mixture was heated to 80 °C, and the stirring was continued
until the aryl fluoride disappeared on TLC. After completion
of the reaction, the mixture was partitioned between Et2O (5
mL) and brine (5 mL), and the organic layer was separated,
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified through silica gel column
chromatography (n-hexane–EtOAc = 6:1) to afford the
desired pure biaryl ether (320 mg, 91% yield).
In summary, an efficient and chemoselective desilylation
method was developed using a catalytic or stoichiometric
amount of DBU,14 and tandem desilylation and SNAr
reactions to furnish biaryl ethers were also accomplished
using the same reagent.15 The protocol involving catalytic
DBU is operationally very straightforward and con-
venient; it does not require careful exclusion of air or
moisture, purification of reagents, or extensive flash chro-
matography. The investigation on the desilylation mecha-
nism and the exact role of DBU in the reaction pathway is
still in progress, and the result will be reported in detail.
Acknowledgment
This work was supported by the Korea Research Foundation Grant
funded by the Korean Government (MOEHRD) (KRF-2005-041-
C00247).
References and Notes
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