Indium tribromide: An efficient catalyst for the silylation of hydroxy groups by the activation of hexamethyldisilazane

Article abstract of DOI:10.1055/s-2006-950322

A variety of substrates containing hydroxy groups have been protected as their corresponding trimethylsilyl ethers using 1,1,1,3,3,3-hexamethyldisilazane in the presence of indium tribromide. The catalyst indium tribromide activates the 1,1,1,3,3,3-hexamethyldisilazane and accelerates the reaction under mild reaction conditions at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950322

PAPER
3831
Indium Tribromide: An Efficient Catalyst for the Silylation of Hydroxy
Groups by the Activation of Hexamethyldisilazane1
I
J
ndium Tr
.
ibromide/1,1
S, 1,3,3,3-Hexa
.
Ya ne: Silylation of
a
Hydroxy
G
d
roups av,* B. V. S. Reddy, A. K. Basak, G. Baishya, A. Venkat Narsaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: yadavpub@iict.res.in
Received 5 April 2006; revised 7 July 2006
8
action under mild reaction conditions and recently indi-
um halides have emerged as mild and water-tolerant
Abstract: A variety of substrates containing hydroxy groups have
been protected as their corresponding trimethylsilyl ethers using
Lewis acids, particularly showing regio-, stereo-, and
1,1,1,3,3,3-hexamethyldisilazane in the presence of indium tribro-
9
mide. The catalyst indium tribromide activates the 1,1,1,3,3,3-hexa- chemoselectivity in various organic transformations.
methyldisilazane and accelerates the reaction under mild reaction
conditions at room temperature.
Compared to conventional Lewis acids, indium tribro-
mide has the advantages of low catalyst loading and mois-
ture stability. We are especially interested in exploring the
Keywords: indium tribromide, 1,1,1,3,3,3-hexamethyldisilazane,
protection, hydroxy group, silylation
potential use of indium tribromide for various organic
1
0
transformations due to its mild and neutral nature. As
part of our ongoing program for the development of new
In the postgenomic age, a premium has been placed on
versatile, complexity-generating reactions in which a
multitude of natural products, drugs, and lead-like com-
pounds can be rapidly assembled and funneled into bio-
11
synthetic methodologies, we wish to report herein an ef-
ficient procedure for the rapid trimethylsilylation of a
wide variety of alcohols using 1,1,1,3,3,3-hexamethyldi-
silazane and a catalytic amount of indium tribromide as
shown in Scheme 1.
2
logical screening programmes. Furthermore, the ability
of chemists to optimize newly discovered lead com-
pounds, as well as to produce analogues or mimics of
biologically active natural products, relies upon the ad-
vancement of current synthetic technologies. Total syn-
thesis of these compounds necessarily involves the
protection and deprotection of a variety of functional
groups. Of these, the hydroxy group is familiar and its
O
O
O
O
HMDS, InBr3
O
O
O
O
CH2Cl2, r.t., 6 h
84%
TMSO
O
HO
O
1
2
3
Scheme 1
protection as its silyl ether is most frequently used. Gen-
erally, the formation of silyl ethers is carried out by the
treatment of alcohols with silyl chlorides or silyl triflates For example, treatment of glucose diacetonide 1 with
4
under basic conditions. However, some of these methods 1,1,1,3,3,3-hexamethyldisilazane in the presence of indi-
frequently suffer from drawbacks, such as lack of reactiv- um tribromide (5 mol%) at room temperature affords the
ity or difficulty in removing the amine salts derived from corresponding trimethylsilyl ether 2 (Scheme 1) in 84%
the reaction of byproduct acids and co-bases during the si- yield without affecting the acetonide groups. The product
1
lylation reaction. Over the course of several decades, a 2 was very clean by H NMR and did not require further
wide variety of methods using 1,1,1,3,3,3-hexamethyldis- purification. In a similar fashion, a wide range of structur-
ilazane (HMDS) as a silylating agent have been devel- ally diverse and functionalized alcohols, such as primary,
oped.5 1,1,1,3,3,3-Hexamethyldisilazane is a stable, secondary, benzylic, phenolic, allylic, and tertiary alco-
commercially available, and inexpensive reagent that is hols underwent smooth reaction with 1,1,1,3,3,3-hexa-
used for the trimethylsilylation of hydrogen-labile sub- methyldisilazane/indium tribromide to give the
strates, giving ammonia as the sole byproduct. Silylation corresponding silyl ether derivatives in excellent yields
using this type of disilazane reagent is nearly neutral and (Table 1). Phenolic and benzylic alcohols reacted little
does not require special precautions. Even though the han- faster than aliphatic alcohols (entries 1, 5, 6, 8, 14, and
dling of this reagent is easy, its main drawback is its poor 15). The acid-sensitive Baylis–Hillman alcohol (entry 17)
silylating power; it needs forceful conditions and long re- was converted into the corresponding trimethylsilyl ether
6
action times. Therefore, to circumvent these problems, derivative 19 without forming any side products. This
considerable attention has been focused on the activation protocol has been used successfully where the acid-sensi-
of 1,1,1,3,3,3-hexamethyldisilazane by using a variety of tive protecting groups like tetrahydropyranyl ethers and
7
catalysts. Lewis acids have been found to catalyze this re- tert-butoxycarbonyl esters were present (entries 10, 11,
and 18). In such cases the reactions were very clean and
did not yield any products from the deprotection of exist-
ing groups.
SYNTHESIS 2006, No. 22, pp 3831–3834
x
x
.x
x
.
2
0
0
6
Advanced online publication: 12.10.2006
DOI: 10.1055/s-2006-950322; Art ID: Z07006SS
Georg Thieme Verlag Stuttgart · New York
©

3832
J. S. Yadav et al.
PAPER
Table 1 Indium Tribromide Catalyzed Silylation of Alcohols by Activation of 1,1,1,3,3,3-Hexamethyldisilazane
Productsa
Time (h)
4.0
Yield (%)
b
Entry
1
Substrate
OH
OTMS
3
4
5
6
89
86
84
81
OH
OTMS
2
3
4
4.5
5.0
4.0
OH
OTMS
OH
OTMS
OH
OTMS
5
6
7
8
4.5
4.0
92
93
OH
Me
OTMS
Me
7
9
6.0
5.0
86
89
OH
OH
OTMS
OTMS
8
9
O
O
10
O
O
O
BnO
O
BnO
OEt
OEt
HO
N
TMSO
11
12
6.0
4.5
89
90
O
O
OH
NH
OTMS
1
0
N
Boc
Boc
Boc
Boc
1
1
2
NH
13
14
4.5
6.0
86
89
OH
OTMS
OH
OTMS
1
1
3
4
15
16
5.0
4.5
82
92
OH
OTMS
OH
OTMS
1
OH
OTMS
15
16
17
17
18
19
4.0
6.0
4.5
94
80
88
OH
OTMS
OH
OTMS
CO2Et
CO2Et
Synthesis 2006, No. 22, 3831–3834 © Thieme Stuttgart · New York

PAPER
Indium Tribromide/1,1,1,3,3,3-Hexamethyldisilazane: Silylation of Hydroxy Groups
3833
Table 1 Indium Tribromide Catalyzed Silylation of Alcohols by Activation of 1,1,1,3,3,3-Hexamethyldisilazane (continued)
b
Entry
Substrate
Productsa
Time (h)
5.0
Yield (%)
OTHP
OTHP
18
20
21
82
86
OH
OTMS
19
5.5
OH
OTMS
a
1
All products were characterized by H NMR, IR, and MS and compared with literature reports.
Isolated and unoptimized yield.
b
The sterically hindered alcohols (Table 1, entries 7, 8, and treated with 1,1,1,3,3,3-hexamethyldisilazane (0.7 mmol)
6 and Scheme 1, 1 ) also reacted very smoothly while in presence of the catalyst (entry 1). The reaction mixture
1
giving the products 9, 10, 18, and 2 in very good yields. In was stirred for a period of two hours and after this time it
the case of N-tert-butoxycarbonyl amino alcohols (entry was found that 85% of 3-phenylpropan-1-ol and 15% of
1
1) the reaction is comparatively faster (4.5 h) and gave menthol had been converted into their respective silyl
the corresponding product 13 in very good yield. The sub- ether derivatives. In the second example, a mixture of
strates like cinnamyl alcohol (entry 4) and hept-3-yn-1-ol benzyl alcohol (1 mmol) and diphenylmethanol (1 mmol)
(entry 19) also underwent smooth conversion. In general, was treated with 1,1,1,3,3,3-hexamethyldisilazane (0.7
the reactions were carried out at room temperature and the mmol), in the presence of the catalyst, for a period of three
solvent used was dichloromethane. All the reactions were hours; in this case 90% of benzyl alcohol and 10% of
completed within 4–6 hours and the obtained yields were diphenylmethanol were converted into their respective si-
in the range 80–94%.
lyl ether derivatives (entry 2). In the third example, an
equimolar mixture of menthol and tert-pentyl alcohol was
treated with 1,1,1,3,3,3-hexamethyldisilazane (0.7 mmol)
and the catalyst for a period of four hours, but only men-
thol was protected as its silyl ether and tert-pentyl alcohol
was unaffected. The above selectivity study shows that
the reactivity order is primary > secondary > benzylic >
tertiary alcohol.
The probable mechanism (Scheme 2) shows that the indi-
um tribromide initially forms a complex A with
1,1,1,3,3,3-hexamethyldisilazane. This complex A will
polarize the Si–N bond to produce the reactive silylating
agent, which on reaction with one mole of alcohol gives
the corresponding silyl ether derivative. In a similar man-
ner, complex B is formed with the catalyst and a second
trimethylsilyl group reacts with a mole of alcohol to give In summary, we have found that indium tribromide is a
the corresponding silyl ether derivative. The mechanism mild and efficient catalyst for the activation of 1,1,1,3,3,3-
clearly shows that one mole of 1,1,1,3,3,3-hexamethyldi- hexamethyldisilazane in the silylation of hydroxy groups.
silazane reacts with two moles of alcohol. Finally, the in-
dium tribromide–ammonia complex evolves of gaseous Table 2 Comparative Study of the Silylation of Alcohols Using
1
,1,1,3,3,3-Hexamethyldisilazane/Indium Tribromide
ammonia and gives the indium tribromide catalyst, which
recycles (Scheme 2).
Entry Alcohols
1
Products
Time Conversion
The selectivity and versatility of the reaction was further
confirmed by application of the general procedure to var-
ious examples (Table 2), in the first of which a mixture of
(h)
(%)
OH
OTMS
2
85
3-phenylpropan-1-ol (1 mmol) and menthol (1 mmol) was
_
15
90
InBr2Br
OH
OTMS
(
Me3Si)2NH
+
InBr3
(Me3Si)2NH
+
A
OH
OTMS
2
3
3
4
ROH
NH3
ROTMS
OH
OTMS
1
0
_
InBr2Br
Br3In-NH3
Me3SiNH2
+
B
ROTMS
ROH
100
0
OH
OH
OTMS
OTMS
Scheme 2
Synthesis 2006, No. 22, 3831–3834 © Thieme Stuttgart · New York

3834
J. S. Yadav et al.
PAPER
This method is applicable to a wide range of alcohols con- Ethyl 2-[Phenyl(trimethylsiloxy)methyl]acrylate (19)
1
H NMR (200 MHz, CDCl ): d = 0.50 (s, 9 H), 1.20 (t, J = 7.0 Hz,
taining multiple functionalities. The experimental condi-
tions are very simple and the isolation of products also
very easy. The highly catalytic nature of indium tribro-
mide and its wide applicability should make this protocol
an attractive alternative over existing methods.
3
3
1
H), 4.10 (q, J = 7.0 Hz, 2 H), 5.50 (s, 1 H), 5.90 (s, 1 H), 6.20 (s,
H), 7.20–7.30 (m, 5 H).
1
,2:5,6-Di-O-isopropylidene-3-O-(trimethylsilyl)-a-D-gluco-
furanose (2)
1
H NMR (200 MHz, CDCl ): d = 0.50 (s, 9 H), 1.25 (2 s, 6 H), 1.50
3
(
s, 3 H), 1.40 (s, 3 H), 3.80–3.90 (m, 2 H), 3.95–4.10 (m, 2 H), 4.22
1H NMR spectra were recorded on a Gemini-200 spectrometer in
(d, J = 3.5 Hz, 1 H), 5.75 (d, J = 3.5 Hz, 1 H).
CDCl using TMS as internal standard. Mass spectra were recorded
3
+
MS (EI): m/z (%) = 332 (M , 10), 317 (20), 305 (12), 271 (18), 259
(
(
on a Finnigan MAT 1020 mass spectrometer operating at 70 eV. All
commercially available reagent-grade chemicals were purchased
from Aldrich and were used as received without further purifica-
tion. All solvents were distilled.
10), 231 (14), 217 (28), 204 (20), 189 (15), 157 (10), 147 (35), 135
10), 129 (20), 103 (12), 85 (15), 73 (100), 59 (25), 45 (20).
1
All products were characterized by H NMR, IR, and MS and com- Acknowledgment
pared with literature reports.
A.K.B. & G.B. thank CSIR-New Delhi for the award of fel-
lowships.
Menthol Trimethylsilyl Ether (9); Typical Procedure
To a mixture of menthol (312 mg, 2 mmol) and HMDS (225 mg, 1.4
mmol) in CH Cl (10 mL) was added the catalyst InBr (36 mg, 0.1
2
2
3
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(
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(
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7
Synthesis 2006, No. 22, 3831–3834 © Thieme Stuttgart · New York