Rapid and efficient trimethylsilyl protection of hydroxyl groups catalyzed by niobium(V) chloride

Article abstract of DOI:10.1080/10426507.2010.482544

An efficient and convenient procedure for the trimethylsilylation of a wide variety of alcohols, including primary, benzylic, secondary, and phenols with hexamethyldisilazane, has been developed. The reactions were carried out at room temperature in the presence of a catalytic amount of niobium(V) chloride and afforded the corresponding trimethylsilyl ethers in high to excellent yields in short time. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon and the
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Rapid and Efficient Trimethylsilyl
Protection of Hydroxyl Groups Catalyzed
by Niobium(V) Chloride
Jun-Tao Hou a , Hong-Li Chen b & Zhan-Hui Zhang a
a The College of Chemistry & Material Science , Hebei Normal
University , Shijiazhuang, China
b Hebei Chemical & Pharmaceutical Vocational Technology College ,
Shijiazhuang, China
Published online: 13 Jan 2011.
To cite this article: Jun-Tao Hou , Hong-Li Chen & Zhan-Hui Zhang (2010) Rapid and Efficient
Trimethylsilyl Protection of Hydroxyl Groups Catalyzed by Niobium(V) Chloride, Phosphorus, Sulfur,
and Silicon and the Related Elements, 186:1, 88-93, DOI: 10.1080/10426507.2010.482544
To link to this article: http://dx.doi.org/10.1080/10426507.2010.482544
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Phosphorus, Sulfur, and Silicon, 186:88–93, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.482544
RAPID AND EFFICIENT TRIMETHYLSILYL PROTECTION
OF HYDROXYL GROUPS CATALYZED BY NIOBIUM(V)
CHLORIDE
Jun-Tao Hou,1 Hong-Li Chen,2 and Zhan-Hui Zhang1
1The College of Chemistry & Material Science, Hebei Normal University,
Shijiazhuang, China
2Hebei Chemical & Pharmaceutical Vocational Technology College, Shijiazhuang,
China
GRAPHICAL ABSTRACT
NbCl5 (5 mol%)
ROH + (Me3Si)2NH
ROSiMe3
r.t.
Abstract An efficient and convenient procedure for the trimethylsilylation of a wide variety
of alcohols, including primary, benzylic, secondary, and phenols with hexamethyldisilazane,
has been developed. The reactions were carried out at room temperature in the presence of a
catalytic amount of niobium(V) chloride and afforded the corresponding trimethylsilyl ethers
in high to excellent yields in short time.
Keywords Hexamethyldisilazane; hydroxyl groups; niobium pentachloride; phenols;
trimethylsilylation
INTRODUCTION
Protection of hydroxyl groups plays an essential role in multistep organic synthesis,
and a large number of reagents and methods have been developed. Among the protecting
groups for protection of alcohols, silyl ethers have been introduced as suitable protection
groups for this purpose due to their easy of formation and cleavage, and their reasonable
stability to the nonacidic media conditions. Trimethylsilylation is one of the most often used
silylating methods. Some silylating agents such as trimethylsilyl chloride, ketene methyl-
trialkylsilyl acetals, allyl silanes, ethyl trimethylsilyl acetate, N,N-bis(trimethylsilylurea),
methyl 3-(trimethylsilyloxy)crotonate, and trimethylsilyl azide have been reported for
trimethylsilyl (TMS) protection of hydroxyl groups.1 The use of some silylating agents
Received 9 February 2010; accepted 30 March 2010.
We are grateful for financial support from the Science Foundation from National Natural Science Founda-
tion of China (20872025), the Nature Science Foundation of Hebei Province (B2008000149), and the Science
Foundation of Hebei Normal University (L20061314).
Address corresponding to Zhan-Hui Zhang, The College of Chemistry & Material Science, Hebei Normal
University, Shijiazhuang 050016, China. E-mail: zhanhui@126.com
88

TRIMETHYLSILYL PROTECTION OF HYDROXYL GROUPS
89
is limited by their unavailability, toxicity, or the laborious processes of purifying the prod-
ucts. Hexamethyldisilazane (HMDS) is a commercially available and cheap reagent, giving
ammonia as the only byproduct, and the products are separated from excess of HMDS by
a simple distillation. However, the low silylating power of HMDS is the main drawback to
its application. Therefore, a variety of reagents have been reported to improve its silylating
power.2–26 Although these procedures worked nicely in many cases, sometimes, however,
some of these procedures are associated with one or more shortcomings such as long re-
action time, low yield, the lack of generality, requirement of excess of reagents, the use of
expensive or less easily available catalysts, and vigorous reaction conditions.
In recent years, niobium(V) chloride has been considered as an efficient Lewis acid
catalyst for a variety of organic transformations.27,28 For example, it has been used to
catalyze regioselective dealkylation of alkyl aryl ethers,29 and in the selective acetylation
of amines and thiols,30 the cyanosilylation of aldehydes,31 chemoselective synthesis of
1,1-diacetates,32 and one-pot Mannich-type reaction,33 as well as deprotection of methoxy
methyl ether.34 It also serves as the catalyst for opening of epoxide rings,35 the synthe-
sis of 1,5-benzodiazepine derivatives,36 bis(indol)alkanes,37 trisubstituted alkenes,38 and
pyrano[3,2-c]quinolines.39 As part of our continuing interest in the development of new
synthetic methodologies,40–44 we report in this article an efficient and convenient procedure
for the trimethylsilylation of alcohols and phenols with HMDS in the presence of a catalytic
amount of NbCl5 at room temperature (Scheme 1).
NbCl5 (10 mol%)
ROSiMe3
ROH + (Me3Si)2NH
r.t.
1
2
3
Scheme 1 Trimethylsilylation of alcohols and phenols catalyzed by NbCl5.
RESULTS AND DISCUSSION
In an optimized procedure, the reaction of 9-fluorenylmethanol with hexamethyld-
isilazane was carried out by varying the catalyst loading in CH2Cl2 at room temperature.
It was found that when increasing the amount of NbCl5 from 1 to 5, 10, and 15 mol%,
the yields increased from 50 to 70, 95, and 96, respectively. Use of 10 mol% of NbCl5 is
sufficient to catalyze the required transformation within a span of 5 min. Any excess of
NbCl5 beyond this loading did not show any further in conversion and yield. Use of less
than the required catalyst loading resulted in low yields. Only trace product was detected
under similar condition in the absence of catalyst at long reaction time (1 h).
The general applicability of this method was further evaluated for structurally diverse
alcohols and phenols under optimized reaction conditions, and the results are depicted in
Table 1. The results clearly show that primary, benzylic, and secondary alcohols as well
as phenols are all good substrates in this reaction, and the corresponding trimethylsilyl
ethers are formed in good to excellent yields. Moreover, when the alcoholic and phenolic
hydroxyl groups are present in the same substrate (Table 1, entry 21), they are transformed
to the corresponding disilyated product. This method was also found to be efficient for
the trimethylsilylation of allylic alcohol (Table 1, entry 15). However, tertiary alcohol
such as triphenylmethanol (Table 1, entry 25) was not silyated during the course of the
reaction. It is noteworthy that the substituents on the phenol moiety play a significant

90
J.-T. HOU ET AL.
Table 1 Protection of alcohols or phenols by formation of trimethylsilyl ethers catalyzed by NbCl5
Entry
Alcohols or phenols
Product
Solvent
Time (min)
Yield (%)a
Ref.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
n-Dodecanol
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
CH2Cl2
CH2Cl2
None
CH2Cl2
None
None
None
CH2Cl2
None
CH2Cl2
None
None
None
CH2Cl2
None
None
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
30
5
4
30
4
5
87
95
95
90
94
93
90
93
95
90
91
95
93
90b
91
92
94
95
70
51
93b
95
90
0
2
3
4
45
5
4
8
8
8
4
9-Fluorenylmethanol
2-Phenylethyl alcohol
1-Adamantanemethanol
2-Phenylethanol
Benzyl alcohol
p-Tolylmethanol
4-Nitrophenylmethanol
Cyclohexanol
Diphenylmethanol
2-Thiophenemethanol
1-Phenylethanol
(4-Methoxyphenyl)methanol
1-o-Tolyloxy-propane-1,3-diol
Cinnamyl alcohol
Phenol
4-Aminophenol
4-Methylphenol
4-Bromophenol
Salicylaldehyde
4-Hydroxymethylphenol
α-Naphthol
β-Naphthol
4-Nitrophenol
Triphenylmethanol
4
30
30
30
30
10
8
20
20
20
15
15
30
30
15
5
13
4
8
8
4
4
9
46
10
11
9
8
12
12
3t
3u
3v
3w
3x
3y
30
60
60
0
aIsolated yield.
bYields refer to disilyated products.
role in this process. The presence of an electron-releasing group, such as methyl and
amino, enhanced the product formation as indicated by short reaction times. Phenol with an
electron-withdrawing group, such as a bromo and aldehyde group (Table 1, entries 19 and
20), required relatively longer reaction times to render lower yield. Nitropnenol (Table 1,
entry 24) failed to convert into the corresponding trimethylsilyl ether when the mixture was
stirred for 1 h in the presence of NbCl5.
Finally, in order to show the efficacy of NbCl5 with respect to the reported catalysts, we
compared the reaction time and yield for trimethylsilylation of α-naphthol. As demonstrated
in Table 2, the yield/time ratios of the present method are better or comparable with the
reported methods.
In conclusion, we have demonstrated that NbCl5 is a highly efficient catalyst for
the trimethylsilylation of a wide range of structurally varied alcohols and phenols. The
advantages, such as mild reaction conditions, short reaction times, and high yields, make
our method a valuable contribution to the existing processes in the field of protection of
hydroxyl groups.
EXPERIMENTAL
IR spectra were obtained using a Bruker Tensor 27 spectrometer instrument. NMR
spectra were taken on a Bruker DRX-500 spectrometer. Elemental analyses were carried
out on a Vario EL III CHNOS elemental analyzer.

TRIMETHYLSILYL PROTECTION OF HYDROXYL GROUPS
91
Table 2 Comparison of the activity of some catalyst in the trimethylsilylation of α-naphthol
Entry
Catalyst
Conditions
Time
Yield (%)
Ref.
1
2
3
4
5
6
7
8
9
10
11
12
13
Silica-FeCl3
Al(H2PO4)3
1,3-Dibromo-5,5-dimethylhydantoin
FeCl3
InBr3
Fe(CF3CO2)3
ZnO
Fe(NO3)3·9H2O/NaI
N-Bromosuccinimide
CuSO4·5H2O
Silica chloride
LiClO4
Solvent-free/rt
Solvent-free/rt
Solvent-free/rt
CH3CN/rt
6 min
7 min
20 min
75 min
4 h
20 min
5 min
8 min
3 h
38 h
4 h
20 min
5 min
93
94
95
85
94
92
90
95
93
50
65
68
95
5
7
9
14
15
16
17
20
23
24
25
26
CH2Cl2/rt
Solvent-free/rt
Solvent-free/rt
CH2Cl2/rt
CH2Cl2/rt
CH3CN/rt
CH2Cl2/rflux
Solvent-free/rt
CH2Cl2/rt
NbCl5
This work
Procedure for Trimethylsilylation of Alcohols or Phenols
A mixture of alcohol or phenol (5 mmol), HMDS (5 mmol), and NbCl5 (0.50 mmol,
10 mol%) in CH2Cl2 (5 mL) or in the absence of solvent was stirred at room temperature.
After completion of the reaction (monitored by TLC or GC), the mixture was diluted
with CH2Cl2 and washed with water. The organic layer was dried over anhydrous MgSO4
and evaporated under reduced pressure. Then the crude product was subjected to column
chromatography over silica gel using hexane as eluent to afford the pure trimethylsilyl
ether.
All of the products were liquids. Compounds 3 except for 3n are known compounds
and their structures were indentified by comparison of their physical and spectroscopic data
with those previously reported. The new product 3n was characterized on the basis of its
elemental analysis and IR, 1H NMR, and 13C NMR spectra.
(9H-Fluoren-9-ylmethoxy)trimethylsilane (3b)
IR (neat): 2956, 1616, 1577, 1477, 1466, 1450, 1379, 1321, 1251, 1109, 999, 896,
1
839, 738 cm−1; H NMR (500 MHz, CDCl3) δH 0.13 (s, 9H), 3.81 (d, J = 8.0 Hz, 2H),
4.08 (t, J = 8.0 Hz, 1H), 7.28 (td, J = 7.5, 1.0 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.62 (dd,
J = 7.5, 1.0 Hz, 2H), 7.74 (d, J = 7.5 Hz, 2H) ppm; Anal. Calcd for C17H20OSi: C, 76.07;
H, 7.51. Found: C, 75.82; H, 7.76.
Trimethylphenethyloxysilane (3e)
IR (neat): 2954, 1604, 1496, 1454, 1382, 1250, 1094, 927, 881, 842, 748, 698 cm−1
;
1H NMR (500 MHz, CDCl3) δH 0.15 (s, 9H), 2.97 (t, J = 7.5 Hz, 2H), 3.84 (t, J = 7.5 Hz,
2H), 7.27–7.36 (m, 5H) ppm; Anal. Calcd for C11H18OSi C, C, 67.98; H, 9.34. Found: C,
68.18; H, 9.20.

92
J.-T. HOU ET AL.
Trimethyl-(4-nitrobenzyloxy)silane (3h)
IR (neat): 2956, 1608, 1520, 1456, 1348, 1251, 1203, 1097, 1014, 842, 748, 688
cm−1; 1H NMR (500 MHz, CDCl3) δH 0.19 (s, 9H), 4.79 (s, 2H), 4.78 (d, J = 8.5 Hz, 2H),
6.19(d, J = 8.5 Hz, 2H) ppm; Anal. Calcd for C10H15NO3Si, C, 53.31; H, 6.71; N, 6.22.
Found: C, 53.50; H, 6.56, N, 6.05.
1-(1,3-Bistrimethylsilanyloxypropoxy)-2-methylbenzene (3n)
IR (neat): 2956, 2873, 1635, 1604, 1593, 1497, 1437, 1250, 1122, 1053, 989, 842, 748
cm−1; 1H NMR (500 MHz, CDCl3) δH 0.13 (s, 9H), 0.16 (s, 9H), 2.23 (s, 3H), 3.61–3.72
(m, 2H), 3.89–4.02 (m, 2H), 4.06–4.10 (m, 1H), 6.81 (d, J = 8.0, 1H), 6.85 (d, J = 8.0,
1H), 7.12–7.15 (m, 2H); 13C NMR (125 MHz, CDCl3) δC −0.48, 0.30, 16.51, 64.55, 69.63,
72.05, 110.95, 120.36, 126.70, 126.78, 130.67, 157.04 ppm; Calcd for C16H30O3Si2: C,
58.84; H, 9.26. Found: C, 59.02; H, 9.05.
Trimethyl-(3-phenylallyloxy)silane (3o)
1
IR (neat): 2956, 1628, 1419, 1122, 1068, 1001, 936, 852, 617 ppm; H NMR (500
MHz, CDCl3) δH 0.13 (s, 9H), 4.31 (dd, J = 5.5, 1.5 Hz, 2H), 6.29 (dt, J = 15.5, 5.5 Hz,
1H), 6.58 (dt, J = 15.5, 1.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.5 Hz, 2H),
7.37 (d, J = 7.5 Hz, 2H) ppm; Calcd for C12H18OSi: C, 69.84; H, 8.79. Found: C, 70.01;
H, 8.52.
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