Microwave-assisted protection of phenols as tert-butyldimethylsilyl (TBDMS) ethers under solvent-free conditions

Article abstract of DOI:10.1081/SCC-200057992

A facile, time-saving procedure to protect phenols with tert-butyldimethylsilyl chloride using imidazole as catalyst under solvent-free conditions is described. Several phenolic compounds with different substitution patterns can be silylated in high yield

Full text of DOI:10.1081/SCC-200057992

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Microwave‐Assisted
Protection of Phenols as
tert‐Butyldimethylsilyl (TBDMS)
Ethers Under Solvent‐Free
Conditions
Erick L. Bastos a , Luiz F. M. L. Ciscato a & Wilhelm
J. Baader a
a Instituto de Química, Universidade de São Paulo ,
São Paulo, Brazil
Published online: 17 Dec 2010.
To cite this article: Erick L. Bastos , Luiz F. M. L. Ciscato & Wilhelm J. Baader (2005)
Microwave‐Assisted Protection of Phenols as tert‐Butyldimethylsilyl (TBDMS) Ethers
Under Solvent‐Free Conditions, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 35:11, 1501-1509, DOI:
10.1081/SCC-200057992
To link to this article: http://dx.doi.org/10.1081/SCC-200057992
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Synthetic Communicationsw, 35: 1501–1509, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200057992
Microwave-Assisted Protection of Phenols
as tert-Butyldimethylsilyl (TBDMS) Ethers
Under Solvent-Free Conditions
Erick L. Bastos, Luiz F. M. L. Ciscato, and Wilhelm J. Baader
´
Instituto de Quımica, Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
Abstract: A facile, time-saving procedure to protect phenols with tert-butyldimethylsilyl
chloride using imidazole as catalyst under solvent-free conditions is described. Several
phenolic compounds with different substitution patterns can be silylated in high yield
with substantially reduced generation of residues, a present goal in organic synthesis.
Keywords: Green chemistry, microwave, phenol protection, silyl ethers
INTRODUCTION
The temporary masking of phenols by a number of silylating agents plays a
fundamental role in modern organic synthesis, polymer development, and
synthetic biochemistry.[1] Since its discovery by Corey and Venkateswarlu,[2]
the tert-butyldimethylsilyl (TBDMS) group is one of the most widely used
protecting groups because of its stability in a variety of organic reactions
and facility by which it can be introduced and removed under mild
conditions. Usually, the reaction between tert-butyldimethylsilyl chloride
(TBDMSCl) and the phenolic compound is performed in the presence of
imidazole or 4-dimethylaminopyridine (DMAP) as catalyst and results in
high yields of TBDMS ether formation.[2,3] However, the procedure for
tert-butyldimethylsilylation of phenols is time consuming and involves the
use of organic solvents such as DMF or THF.[4]
Received in the USA January 27, 2005
Address correspondence to Wilhelm J. Baader, Instituto de Quımica, Universidade
´
de Sa˜o Paulo, Sa˜o Paulo, SP, Av. Prof. Lineu Prestes, 748 Bl. 12 Sup., 05508-900
Brazil; E-mail: wjbaader@iq.usp.br
1501

1502
E. L. Bastos, L. F. M. L. Ciscato, and W. J. Baader
In recent developments, the use of microwave irradiation (mW) has
become a very popular tool to simplify and improve organic reactions,
because the desired product is often obtained in high yield and shorter
reaction times. Furthermore, the reactions might be performed under
solvent-free conditions and therefore be considered green chemistry.[5]
Khalafi-Nezhad et al. described a method for silylation of alcohols and
phenols using triisopropylsilyl chloride (TIPSCl) and imidazole under
microwave irradiation.[6] Hexamethyldisiazane (HMDS) was also used as
silylanting agent in microwave-assisted protection of phenols.[7,8] Neverthe-
less, the ease of deprotection of the TBDMS group with several substances
under mild conditions, including tetrabutylammonium fluoride (TBAF),[2]
KF,[9] KOH/EtOH,[10] LiCl,[11] ZrCl4,[12] and Cs2CO3,[13] among others,[1]
is an advantage in the preparation of several organic compounds, especially
in the synthesis of natural products.[14] Recently, a method of tert-butyldi-
methylsilylation of phenols using microwave dielectric heating and iodine
as catalyst has been reported. However, high microwave power, large
TBDMSCl excess, and workup with organic solvents are required.[15]
In this article, we report the conversion in high yield of several phenolic
compounds to their corresponding TBDMS ethers using microwave-assisted
synthesis in solvent-free conditions. Several variables were studied to
determine optimal experimental conditions: (i) microwave power output,
(ii) the time of irradiation, (iii) the amount of silylating agent, and (iv) the
amount of catalyst required to obtain high yields of conversion.
RESULTS AND DISCUSSION
The reaction involves the dielectric heating of a mixture of TBDMSCl, the
phenolic compound and imidazole, in absence of solvent. After 1 min of
irradiation, with any microwave power, the reaction mixture (initially as a
mixture of solids) melts in two phases. The yields obtained on protection of
3-hydroxybenzaldehyde as TBDMS ether after 1 min of irradiation varied
slightly at the microwave power range between 180 W and 270 W. When
power values higher than 270 W are used, lower yields are obtained (Table 1).
Several conditions were tested to assess the efficiency of the reaction
(Table 2). Optimum experimental conditions were obtained using a small
excess of TBDMSCl (1.2 eq.) and 2 eq. of imidazole. The use of a large
excess of imidazole results in the complete conversion to the silylated
product. However, direct distillation of the product is difficult under this
condition, demanding an aqueous workup before purification. Large excess
of the silylating agent should also be avoided as it results in a white fume
from the reaction flask, with no significant increase in the yield. This fume
is also observed if TBDMSCl is irradiated alone, which indicates that it
originates from the silylating agent decomposition.

Microwave-Assisted Protection of Phenols
Table 1. Effect of microwave power on reaction yields
1503
of 3-hydroxybenzaldehyde with TBDMSCl (1.2 eq) and
imidazole (2 eq.) after 1 min of irradiation
Product
Power (W)
Yield (%)a
90
180
270
360
450
36
74
81
74
61
aGC yields
The dependence of the irradiation time on the formation of 3-(tert-
butyldimethylsilanyloxy)benzaldehyde was also investigated. As depicted in
Figure 1, the higher efficiency is obtained with an irradiation time of 3 to
6 min. Longer reaction times lead to a darkening of the reaction mixture
and slightly lower yields of the silyl ethers are obtained.
We have examined the method’s consistency with a variety of phenolic
substrates with different substitution patterns (Table 3). In all cases, silyl
ethers were obtained in good to excellent yields using low irradiation power
(90 W) for 2 min and, after a cooling period, 2 min more at 180 W. The use
of two heating cycles results in better yields than continuous irradiation at
1
90 or 180 W for 4 min. Products were identified by H-NMR and 13C-NMR
spectra and comparison with previously reported spectroscopic data.[4,6]
Purity was measured by gas chromatography of the distillated products. The
Table 2. Effect of reactant concentration on protection of
3-hydroxybenzaldehyde as TBDMS ethera
Product
TBDMSClb
Imidazoleb
Yield (%)
1.0
1.2
2.0
1.0
1.2
1.5
2.0
1.0
1.5
1.0
1.0
1.0
2.0
2.0
2.0
2.0
3.0
3.0
71c
81c
88c
87c
97c
98c
97c
90d
99d
aFor experimental conditions, see representative procedure.
bIn equivalents.
cGC yield after direct distillation.
dGC yield after aqueous workup, extraction, and distillation.

1504
E. L. Bastos, L. F. M. L. Ciscato, and W. J. Baader
Figure 1. Dependence of 3-(tert-butyldimethylsilanyloxy)benzaldehyde formation
on the irradiation time at 180 W, using TBDMSCl (1.2 eq.) and imidazole (2.0 eq.).
The yields represent isolated silylated product after direct distillation. The error bars
indicate mean values + sd of at least three experiments.
utility of the method was also confirmed by the monosilylation of catechol and
the protection, as TBDMS silyl ether, of resorufin (entry 10), a widely used
fluorescent indicator.[16]
In summary, we have developed a mild and efficient method for the pro-
tection of phenolic compounds as TBDMS ethers. This method does not
require long reaction times as the dielectric heating provided by microwave
irradiation is used to accelerate the process. Moreover, the reaction is
performed under solvent-free conditions and does not require aqueous
workup. Silyl ethers are obtained in good to excellent yields upon low-
power irradiation (90 W) for 2 min, a cooling period, and then followed by
2 min irradiation at 180 W, using small excess of TBDMSCl (1.2 eq.) and 2
eq. of imidazole. Thus, the use of this protocol for the preparation of
TBDMS ethers substantially reduces the generation of residues, which is a
present goal in organic synthesis.
EXPERIMENTAL
General
All reactants were purchased at highest commercial quality and used
without any further purification. 3-(2-Methylpropenyl)phenol and 3-(3-
methyl-2-butenyl)phenol were prepared as described elsewhere.[4] Product
formation was followed on a Shimadzu CG14A gas chromatograph

Microwave-Assisted Protection of Phenols
1505
Table 3. Microwave-assisted protection of phenols with TBDMSCl/imidazole under
solvent-free conditionsa
Entry
1
Substrate
Product
Yield (%)b
89
2
3
86
97
4
93
5
6
7
91
88
84
8
92
(continued)

1506
E. L. Bastos, L. F. M. L. Ciscato, and W. J. Baader
Table 3. Continued
Entry
9
Substrate
Product
Yield (%)b
76
79
10
aFor experimental conditions, see representative procedure.
bGC yield after direct distillation.
coupling with a flame ionization detector (FID), using a capillary column
(Supelco SBP-1701, fused silica 30 m ꢀ 0.25 mm ꢀ 0.25 mm film
thickness). The purification of the products was carried out using a bulb-
to-bulb distillatory Kugelrohr apparatus (Bu¨chi glass oven B-580). The
1H and 13C spectra were obtained in CDCl3 using tetramethylsilane
(TMS) as internal reference on a Bruker AC-200F and the mass spectra
on a CG-MS Hewlett-Packard 5890/5988.
Representative Procedure
In a round-bottom flask, up to 15 g of phenolic compound, tert-
butyldimethylsilyl chloride (1.2 eq.), and imidazole (2 eq.) are combined.
This flask is put into a beaker, surrounded by vermiculite, and placed inside
of a Samsung (MW6730 W, 900 W) microwave oven at 10 cm from the
internal plate border. The reaction mixture is then heated for 2 min on a
power setting of 10% (ꢀ90 W). Once the heating cycle is complete, two
phases are formed inside the flask. After a cooling period, the reaction
mixture is heated again on a power setting of 20% (ꢀ180 W) until the
reactant is completely consumed, as determined by TLC. The products
are purified by bulb-to-bulb distillation under reduced pressure using a
Kugelrohr (Bu¨chi glass oven B-580) apparatus. If an aqueous workup is
required, the reaction mixture is poured into water and extracted with Et2O.
The combined organic phases are dried over anhydrous MgSO4 and the
solvent is evaporated under reduced pressure. The crude products are
purified by distillation with a Kugelrohr (Bu¨chi glass oven B-580) apparatus
under reduced pressure. All microwave irradiations are carried out in an open
system.

Microwave-Assisted Protection of Phenols
Characterization Data
1507
(3-Bromophenoxy)tert-butyldimethylsilane (1). Bp (2 mmHg): 119–1288C.
1
Rf (SiO2, hexane/ethyl acetate; 5/1): 0.92. H-NMR (200 MHz, CDCl3) d:
7.61–7.34 (m, 4H), 1.52 (s, 9H), 1.01 (s, 6H). MS m/z: 286 (Mþ). Anal.
calcd. for C12H19BrOSi: C, 50.17; H, 6.67. Found: C, 50.56; H, 6.81.
(4-Bromophenoxy)tert-butyldimethylsilane (2). Bp (3 mmHg): 119–
1258C. Rf (SiO2, hexane/ethyl acetate; 5/1): 0.90. 1H-NMR (200 MHz,
CDCl3) d: 7.35 (d, J ¼ 8.56 Hz, 2H), 6.75 (d, J ¼ 8.56 Hz, 2H), 1.37
(s, 9H), 1.07 (s, 6H). MS m/z: 286 (Mþ). Anal. calcd. for C12H19BrOSi: C,
50.17; H, 6.67. Found: C, 50.54; H, 6.78.
3-(tert-Butyldimethylsilanyloxy)benzaldehyde (3). Bp (2 mmHg): 28–
1358C. Rf (SiO2, hexane/ethyl acetate; 5/1): 0.95. 1H-NMR (200 MHz,
CDCl3) d: 9.99 (s, 1H), 7.65–6.99 (m, 4H), 0.90 (s, 9H), 0.12 (s, 6H).
13C-NMR (50 MHz, CDCl3) d: 192.17, 158.02, 137.87, 130.07, 126.56,
123.55, 119.85, 25.58, 18.16, 24.46. MS m/z: 236 (Mþ). Anal. calcd. for
C13H20O2Si: C, 66.05; H, 8.53. Found: C, 66.19; H, 8.61.
4-(tert-Butyldimethylsilanyloxy)benzaldehyde (4). Bp (2 mmHg):
120–1308C. Rf (SiO2, hexane/ethyl acetate; 5/1): 0.89. 1H-NMR
(200 MHz, CDCl3) d: 9.86 (s, 1H), 7.75 (d, J ¼ 8.79 Hz, 2H), 6.91
(d, J ¼ 8.79, 2H), 0.98 (s, 9H), 0.23 (s, 6H). MS m/z: 236 (Mþ). Anal.
calcd. for C13H20O2Si: C, 66.05; H, 8.53. Found: C, 66.09; H, 8.55.
3-(tert-Butyldimethylsilanyloxy)benzoic acid methyl ester (5). Bp
(2 mmHg): 125–1288C. Rf (SiO2, hexane/ethyl acetate; 5/2): 0.88.
1H-NMR (200 MHz, CDCl3) d: 7.64–6.99 (m, 4H), 3.89 (s, 3H), 0.97
(s, 9H), 0.19 (s, 6H). MS m/z: 266 (Mþ). Anal. calcd. for C14H22O3Si: C,
63.12; H, 8.32. Found: C, 63.21; H, 8.40.
tert-Butyldimethyl[3-(2-methyl-propenyl)phenoxy]silane (6). Bp
(3 mmHg): 132–1388C. Rf (SiO2, hexane/ethyl acetate; 5/1): 0.85. 1H-
NMR (200 MHz, CDCl3) d: 6.90 (m, 4H), 6.17 (s, 1H), 1.82 (s, 3H), 1.79
(s, 3H), 0.94 (s, 9H), 0.21 (s, 6H). MS m/z: 262 (Mþ). Anal. calcd. for
C16H26OSi: C, 73.22; H, 9.98. Found: C, 73.44; H, 10.09.
tert-Butyldimethyl[3-(3-methyl-but-2-enyl)phenoxy]silane (7). Bp
(0.5 mmHg): 100–1108C. Rf (SiO2, hexane/ethyl acetate; 1/1): 0.68.
1H-NMR (200 MHz, CDCl3) d: 6.96–6.43 (m, 4H), 5.13–5.12 (m, 1H),
3.09 (d, J ¼ 7.5 Hz, 2H), 1.56 (s, 3H), 1.52 (s, 3H), 0.82 (s, 9H),
0.06 (s, 6H). 13C-NMR (50 MHz, CDCl3) d: 155.6, 143.3, 132.4, 129.1,
123.1, 121.3, 120.1, 117.2, 34.2, 25.8, 25.7, 18.2, 17.9, 24.4. MS m/z: 276
(Mþ). Anal. calcd. for C17H28OSi: C, 73.85; H, 10.21. Found: C, 74.03; H,
10.29.
tert-Butyldimethyl(3-nitrophenoxy)silane (8). Bp (2 mmHg): 110–
1208C. Rf (SiO2, hexane/ethyl acetate; 5/1): 0.68. 13C-NMR (50 MHz,
CDCl3) d: 156.20, 149.22, 130.37, 122.12, 115.99, 110.67, 25.82, 25.73,
18.21, 17.99, 24.47. MS m/z: 253 (Mþ). Anal. calcd. for C12H19NO3Si: C,
56.88; H, 7.56; N, 5.53. Found: C, 56.91; H, 7.60; N, 5.59.

1508
E. L. Bastos, L. F. M. L. Ciscato, and W. J. Baader
2-(tert-Butyldimethylsilanyloxy)phenol (9). Bp (2 mmHg): 119–1288C.
1
Rf (SiO2, hexane): 0.36. H-NMR (200 MHz, CDCl3) d: 7.21–7.02 (m, 4H),
5.69 (bs, 1H), 1.03 (s, 9H), 0.26 (s, 6H). MS m/z: 224 (Mþ). Anal. calcd.
for C12H20O2Si: C, 64.24; H, 8.98. Found: C, 64.39; H, 9.06.
7-(tert-Butyldimethylsilanyloxy)resorufin (10). Bp (2 mmHg): 135–
1458C. Rf (SiO2, methanol): 0.51. 1H-NMR (200 MHz, CDCl3) d: 7.61
(s. 1H), 7.05 (m, 2H), 6.62 (bs, 3H), 0.90 (s, 9H), 0.07 (s, 6H). MS m/z:
327 (Mþ). Anal. calcd. for C18H21NO3Si: C, 66.02; H, 6.46; N, 4.28.
Found: C, 66.29; H, 6.67; N, 4.35. 7-(tert-Butyldimethylsilanyloxy)resorufin
exhibits no considerable fluorescence emission; however, the corresponding
anion, formed by TBAF-mediated deprotection, shows strong fluorescence
with a maximum of lem ¼ 593 nm.[16]
ACKNOWLEDGMENT
We thank Luiz Fernando da Silva Junior and Dieter Weiß for a critical reading
of the manuscript and FAPESP (00/06652-0, 01/07477-0) and CAPES for
substantial financial support.
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