Nonionic superbase-catalyzed silylation of alcohols

Article abstract of DOI:10.1021/jo9701492

Herein we report a very effective and mild procedure for the silyl protection of a wide variety of substrate alcohols, including primary, secondary, allylic, propargylic, benzylic, hindered secondary, tertiary, acid-sensitive, and base-sensitive alcohols and also hindered phenols. The silylation reagent used is tert-butyldimethylsilyl chloride (TBDMSCl) and the catalyst is P(MeNCH₂CH₂)₃N, 1b, both of which are commercially available. The reactions are carried out in acetonitrile from 24 to 40 °C and on rare occasions in DMF from 24 to 80 °C. The effect of solvent, catalyst concentration, and temperature and reaction time on the silylation of alcohols and the excellent compatibility of our method with a variety of functional groups is discussed. An efficient method for recycling the catalyst is also presented. Although representative primary alcohols, secondary alcohols, and phenols were silylated using the more sterically hindered reagent tert-butyldiphenylsilyl chloride (TBDPSCl) in the presence of lb as a catalyst, tertiary alcohols were recovered unchanged.

Full text of DOI:10.1021/jo9701492

J . Org. Chem. 1997, 62, 5057-5061
5057
Non ion ic Su p er ba se-Ca ta lyzed Silyla tion of Alcoh ols
Bosco A. D’Sa, Dale McLeod, and J ohn G. Verkade*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received J anuary 27, 1997X
Herein we report a very effective and mild procedure for the silyl protection of a wide variety of
substrate alcohols, including primary, secondary, allylic, propargylic, benzylic, hindered secondary,
tertiary, acid-sensitive, and base-sensitive alcohols and also hindered phenols. The silylation reagent
used is tert-butyldimethylsilyl chloride (TBDMSCl) and the catalyst is P(MeNCH2CH2)3N, 1b, both
of which are commercially available. The reactions are carried out in acetonitrile from 24 to 40 °C
and on rare occasions in DMF from 24 to 80 °C. The effect of solvent, catalyst concentration, and
temperature and reaction time on the silylation of alcohols and the excellent compatibility of our
method with a variety of functional groups is discussed. An efficient method for recycling the
catalyst is also presented. Although representative primary alcohols, secondary alcohols, and
phenols were silylated using the more sterically hindered reagent tert-butyldiphenylsilyl chloride
(TBDPSCl) in the presence of 1b as a catalyst, tertiary alcohols were recovered unchanged.
In tr od u ction
transformation. A problem with TBDMSCl and TBDP-
SCl has been the difficulty of silylating hindered second-
ary alcohols, tertiary alcohols, and hindered phenols. An
advantage of the TBDPS group is that its phenyl group
is a chromophore that facilitates the detection of products
on chromatograms by spectrophotometric methods; a
feature not shared by the TBDMS group. Moreover, the
TBDPS moiety is more robust than the TBDMS group,
and hence efficient introduction of the former moiety is
of particular interest in organic synthesis. Recently,
Hardinger et al. reported the silylation of primary and
secondary alcohols in 69-99% yield using TBDPSCl in
DMF with AgNO3, NH4NO3, or NH4ClO4.11d
The importance of protecting the hydroxyl group in
synthetic organic chemistry is reflected by the currently
rather continuous appearance in the literature of syn-
theses of biologically active molecules possessing hy-
droxyl groups. Among the many trialkylsilyl reagents
used to protect such groups, tert-butyldimethylsilyl chlo-
ride (TBDMSCl) and tert-butyldiphenylsilyl chloride (TB-
DPSCl) have been the most popular, ever since the
introduction of TBDMSCl in 1972 by Corey1 and of
TBDPSCl in 1975 by Hanessian.2 Sterically hindered
reagents of this type confer augmented stability on the
derivatized substrate over the trimethylsilylated ana-
logues. Thus the larger tert-butyl substituent hinders
attack at the silicon atom of the silyl ether, thereby
rendering the protected substrate more stable toward
hydrolysis in weakly acidic or basic media and toward
oxidative and reductive conditions frequently encoun-
tered in subsequent synthetic steps.3 The stability and
the facile specific removal of these protecting groups
under very mild conditions have been major factors in
their widespread use in the synthesis of a variety of
compounds including ribonucleosides,4 carbohydrates,5
analogues of thromboxane A2,6 leukotrienes,7 steroids,8
and antibiotics.9
Herein we report a very effective and mild procedure
for the silyl protection of a wide variety of OH-containing
substrates, including primary, secondary, allylic, prop-
argylic, benzylic, hindered secondary, tertiary, acid-
sensitive, and base-sensitive alcohols and also hindered
phenols. For this purpose the commercially available and
relatively inexpensive silylating reagent TBDMSCl is
used in the presence of the commercially available
catalyst 1b which was first reported from our laborato-
ries.12 The reactions are carried out in acetonitrile as a
solvent from 24 to 40 °C, and on rare occasions in DMF
from 24 to 80 °C. The effect of solvent, catalyst concen-
tration, reaction time, and temperature on the silylation
of alcohols is discussed, and an efficient method for
A variety of methods have been reported for the
derivatization of alcohols with the TBDMS10 and TB-
DPS11 moieties. Currently, preparations of the corre-
sponding silyl ethers are most satisfactorily and popu-
larly achieved by reacting the alcohol with a molar excess
of imidazole using dimethyl formamide as a solvent.1,2
Other solvents were found to be unsuitable for this
(10) (a) Kim, S.; Chang, H. Synth. Commun. 1984, 14, 899. (b) Kim,
S.; Chang, H. Bull. Chem. Soc. J pn. 1985, 58, 3669. (c) Aizpurua, J .
M.; Palomo, C. Tetrahedron Lett. 1985, 26, 475. (d) Lissel, M.; Weiffen,
J . Synth. Commun. 1981, 11, 545. (e) Lombardo, L. Tetrahedron Lett.
1984, 25, 227. (f) Chaudhary, S. K.; Hernandez, O. Tetrahedron Lett.
1979, 99. (g) Olah, G. A.; Gupta, B. G.; Narang, S. C.; Malhotra, R. J .
Org. Chem. 1979, 44, 4272. (h) Kita, Y.; Haruta, J .; Fujii, T.; Segawa,
J .; Tamura, Y. Synthesis 1981, 451. (i) Veysoglu, T.; Mitscher, L. A.
Tetrahedron Lett. 1981, 22, 1299. (j) Morita, T.; Okamoto, Y.; Sakurai,
H. Tetrahedron Lett. 1980, 21, 835. (k) Mawhinney, T. P.; Madson, M.
A. J . Org. Chem. 1982, 47, 3336. (l) J ohnson, D. A.; Taubner, L. M.
Tetrahedron Lett. 1996, 37, 605. (m) Barton, T. J .; Tully, C. R. J . Org.
Chem. 1978, 43, 3649. (n) Corey, E. J .; Cho, H.; Rucker, C.; Hua, D.
H. Tetrahedron Lett. 1981, 22, 3455.
(11) (a) Golinski, M.; Brock, C. P.; Watt, D. S. J . Org. Chem. 1993,
58, 159. (b) Mazur, P.; Nakanishi, K. J . Org. Chem. 1992, 57, 1047. (c)
Gooding, O. W.; Beard, C. C.; J ackson, D. Y.; Wren, D. L.; Copper, G.
F. J . Org. Chem. 1991, 56, 1083. (d) Hardinger S. A.; Wijaya, N.
Tetrahedron Lett. 1993, 34, 3821. (e) Detty, M. R.; Seidler, M. R. J .
Org. Chem. 1981, 46, 1283.
X Abstract published in Advance ACS Abstracts, J uly 1, 1997.
(1) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,
6190.
(2) Hanessian, S.; Lavallee, P. Can. J . Chem. 1975, 53, 2975.
(3) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley and Sons, Inc.: New York, 1991; pp
77-84, 414-416.
(4) Ogilvie, K. K.; Sadana, K. L.; Thompson, E. A.; Quilliam, M. A.;
Westmore, J . B. Tetrahedron Lett. 1974, 2861.
(5) Shin, J . E. N.; Perlin, S. A. Carbohydr. Res. 1979, 76, 165.
(6) Corey, E. J .; Ponder, J . W.; Ulrich, P. Tetrahedron Lett. 1980,
21, 137.
(7) Corey, E. J .; Goto, G. Tetrahedron Lett. 1980, 21, 3463.
(8) Beloeil, C. J .; Esnault, C.; Fetizon, M.; Henry, R. Steroids 1980,
35, 281.
(12) Schmidt, H.; Lensink, C.; Xi, S. K.; Verkade, J . G. Z. Anorg.
Allg. Chem. 1989, 578, 75.
(9) Nicolaou, C. K.; Roland, L. M. J . Org. Chem. 1981, 46, 1506.
S0022-3263(97)00149-7 CCC: $14.00 © 1997 American Chemical Society

5058 J . Org. Chem., Vol. 62, No. 15, 1997
D’Sa et al.
Ta ble 1. Con d ition s for th e P r ep a r a tion of TBDP S
Eth er s Usin g 1b a s a Ca ta lysta
equiv eluent time temp
%
alcoholb
of 1b ratioc (h) (°C) solvent yield
8
0.1
0.2
0.3
0.1
0.2
0.2
0.5
85:15
80:20
85:15
85:15
80:20
80:20
80:20
80:20
12
24
24
15
24
24
24
24
24 DMF
24 DMF
50 DMF
24 DMF
24 DMF
50 DMF
80 neat
80 neat
98
90
98
98
67
98
0
10
15
16
cyclohexanol
cyclohexanol
linalool
recycling the catalyst is presented. Representative pri-
mary alcohols, secondary alcohols, and phenols were
silylated using tert-butyldiphenylsilyl chloride (TBDPSCl)
in the presence of 1b as a catalyst, but tertiary alcohols
were recovered unchanged in this reaction. A prelimi-
nary communication of our silylation results with TB-
DMSCl in the presence of 1b has appeared.13
1-methylcyclohexanol 0.5
0
a
No attempt was made to maximize yields by optimizing the
b
reaction time, the temperature, and the concentration of 1b. The
alcohols are commercially available and were used as received.
cHexanes/ethyl acetate on a silica gel column.
of imidazole, no Et3N, 3 h, 71%14). Using TBDMSOTf to
silylate (()-9 in the presence of 1.1 equiv Et3N at 24 °C
gave a 99% yield of silylated product in 3 h.
The ratio of the yields of the chromatographically
separated10f silylation products from the combination of
1.0 equiv of TBDMSCl with the diol in reaction 2 was
Resu lts
Tables 1 and 2 summarize the efficiency, the functional
group compatibility, and scope of our procedure using
alcohols 4-21 as candidate substrates in reaction 1. The
97:3 A:C using 0.1 equiv of 1b and 1.0 equiv of Et3N in
MeCN after 12 h. This compares with literature ratios
of 59:11:30 A:B:C (2.2 equiv of imidazole, no Et3N, DMF,
12 h)10f and 95:5 A:C (0.04 equiv of DMAP, 1.1 equiv of
Et3N, CH2Cl2, 12 h).10f
Reaction 3 is not chemoselective and proceeded in poor
yield despite the use of a silanized (2% TMSCl in
hexanes) silica gel column (eluent: 50/50 pentane:ether
TBDPS silylation of benzyl alcohol was carried out using
0.1 mmol of 1b as a catalyst, 1.0 mmol of benzyl alcohol,
and 1.1 mmol each of Et3N and TBDPSCl in 3.0 mL of
solvent at 50 °C over a period of 24 h under a nitrogen
atmosphere. The influence of solvents on the yield of
TBDPS benzyl ether in reaction 1 can be seen in the
following data: benzene, 20%; acetonitrile, 22%; THF,
24%; DMF, 99%. This result prompted us to compare
the yields of TBDPS cyclohexyl ether obtained with
different silylation catalysts under the same conditions.
Thus silylation of 2.0 mmol of cyclohexanol with 2.1 mmol
each of TBDPSCl and triethylamine in the presence of
0.4 mmol of the silylation catalyst in 3.0 mL of DMF at
50 °C for 24 h under N2 revealed the following yields after
workup as described in method B in the Experimental
Section: DMAP, 36%; DBU, 73%; TMG, 36%; 1b, 98%.
Using the convenient solvent MeCN, reaction 1 for the
silylation of (()-menthol [(()-9] with TBDMSCl at 24 °C
in the presence of 1b is effected in 99% yield in 3 h (Table
2). Literature reports of this reaction at the same
temperature consistently utilize the less convenient
solvent DMF for alternate catalysts (DBU, 20 min,
91%;10b TMG, 1 h, 88%;10a DMAP, 12 h, 99%;10f 2 equiv
followed by 10% addition of ether by volume after each
50 mL of eluent passage, until 50 mL of ether was
consumed). Thus a 14% yield of D was realized as a
white solid in the initial fraction and 12% of E as a yellow
solid was obtained in the second.
The combination of o-hydroxybenzoic acid with 1.0
equiv of TBDMSCl, 1.0 equiv Et3N, and 0.2 equiv 1b in
MeCN gave, after 3 h at 24 °C, only starting materials
on chromatographic workup on a silanized column (elu-
ent: 80:20 hexanes:EtOAc followed after 50 mL of eluent
passage by 50 mL of 70:30 eluent and then 50 mL of 60:
40 eluent).
Discu ssion
The generally favorable effect of polar solvents on the
silylation of alcohols under the conditions employed here
may be rationalized on the basis of ions 2a and 2b being
formed as an active intermediate in the reaction involving
1b and the corresponding silyl chloride. Although we
were unable to detect 2a and 2b by 1H and 31P NMR
spectroscopies, its analogue 3a was observed and char-
(14) Kendall, P. M.; J ohnson, J . V.; Cook, C. E. J . Org. Chem. 1979,
44, 1423.
(13) D’Sa, B. A.; Verkade, J . G. J . Am. Chem. Soc. 1996, 118, 12832.

Nonionic Superbase-Catalyzed Silylation of Alcohols
J . Org. Chem., Vol. 62, No. 15, 1997 5059
Ta ble 2. Con d ition s for th e P r ep a r a tion of TBDMS
Eth er s Usin g 1b a s a Ca ta lysta
Sch em e 1
equiv
of 1b
eluent
ratioc
time
(h)
temp
(°C)
%
yield
alcoholb
solvent
4
0.2
0.2
d
95:5
95:5
95:5
95:5
95:5
95:5
95:5
97:3
100:0
95:5
80:20
100:0
100:0
92:8e
92:8e
90:10
95:5
100:0
90:10
90:10
90:10
90:10
90:10
80:20
80:20
85:15
85:15
85:15
3
3
3
3
2
0.3
3
0.2
3
12
2
4
12
0.2
0.2
0.2
0.2
2
0.2
0.2
24
24
24
3
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
80
80
80
24
40
40
40
40
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
CH3CN
CH3CN
CH3CN
CH3CN
neat
DMF
DMF
neat
CH3CN
DMF
99
73
72
30
99
99
99
99
99
90
99
50
85
80
96
96
99
88
90
90
60
80
60
42
86
86
35
37
5
6
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.2
0.36
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
0.2
0.2
0.2
0.2
(()-7
8
(()-9
11
12
13
(()-14
15
16
17
formation of a five-coordinate intermediate, with the
unusual feature that the nucleophilic atom (Nax) com-
pletes its inversion from its already nearly planar ster-
eochemistry15 in the bridgehead position of the bicyclic
structure 1b. Apparently the augmented nucleophilicity
and basicity of phosphorus in molecules of type 1 stem-
ming from the transannular bonding that accompanies
the reaction play an important role in the rate of
formation and stability, respectively, of cations of type 2
and 3. It is worth noting in this respect that 1a is more
basic than 1b for reasons that are not obvious.16
Under the conditions employed for the silylation of
alcohols in this work, we believe that the silyl group of
2a and 2b is activated by loose binding of the ion pair,
thus facilitating attack of a nucleophile on the silicon,
and subsequently affording the silyl ether as shown for
2b in Scheme 1. This mechanism is analogous to that
proposed for silylations involving DBU.10b
(()-18
19
(()-20
(()-21
12
3
3
CH3CN
CH3CN
CH3CN
f
3
a
No attempt was made to maximize yields by optimizing
b
reaction times, the temperature, and the concentration of 1b. All
the alcohols, except for 21, are commercially available and were
used as received. Alcohol 21 was prepared by the reduction of the
corresponding ketone by a method analogous to that used for other
ketones.21 c Hexanes/ethyl acetate on a silica gel column unless
otherwise specified. 0.2 equiv of 1c was used. e A silica gel column
d
neutralized with 1% Et3N in hexanes was used. f 0.2 equiv of 3b
was used.
In Table 1 it is seen that a fatty alcohol such as n-octyl
alcohol (8) was silylated at room temperature and
secondary alcohols such as 9 and cyclohexanol were
silylated in high yields at 55 °C in DMF using TBDPSCl.
The yield of the TBDPS ether of cyclohexanol obtained
by our method (Table 1) was comparable with that
obtained in Hardinger’s procedure which involves the use
of TBDPSCl in DMF with AgNO3, NH4NO3, or NH4ClO4.11d
Moreover, phenols and tertiary alcohols (unspecified) in
Hardinger’s work11d were recovered unreacted according
to that report, whereas phenol 10 was silylated in high
yield using our approach. As in Hardinger’s work,
tertiary alcohols such as linalool and 1-methylcyclohex-
anol were also recovered unreacted under our conditions
(Table 1). Recently, an efficient selective desilylation of
TBDMS phenolic ethers in the presence of TBDPS
phenolic ethers using 5 mol % of PdCl2(CH3CN)2 was
reported.17 This information should promote the use of
the TBDMS and TBDPS moieties as a protecting groups
for phenols.
acterized by 1H and 31P NMR spectroscopies as we
reported in a preliminary account.13 An analogous sily-
lating intermediate derived from the catalysts DMAP,10f
DBU,10b and TMG10a has been postulated but none of
these intermediates was observed directly. It should be
noted that Et3N does not catalyze alcohol silylation.10f It
was found in the present work that the TBDMS silylation
of 21 using 1b as a catalyst provided an 86% yield of the
silylated product (Table 2) whereas the same reaction run
without 1b gave only a 35% yield. Cation 3b does not
function as the catalyst under our reaction conditions,
since the yield of the TBDMS ether of 21 was almost the
same (37%) when 3b was employed. These studies
indicate that the P-silylating intermediates 2a and 2b
may be present in very small concentrations (probably
due to steric hindrance of the methyl groups on 1b), thus
1
precluding detection by H and 31P NMR spectroscopies.
Partial formation of the transannular PNax bond in the
intermediate 2a and 2b may reflect both the increased
strain and decreased entropy associated with the estab-
lishment of three five-membered rings in these cations,
which counterbalance the electron-withdrawing power of
the apical substituent. Another factor possibly favoring
transannular interaction when 1b is electrophilically
attacked by the silyl reagent is the nearly planar con-
figuration of Nax in 1c15 (and very probably in 1b). The
transannulation process that accompanies the formation
of intermediates 2a and 2b can be viewed as an SN2
It has been reported that the silylation of 4 using 0.2
equiv of TMG in the presence of TBDMSCl and Et3N
resulted in an 87% yield of the silylated product at room
temperature in acetonitrile,10a whereas this silylation
using 0.33 equiv of DMAP in the presence of TBDMSCl
and Et3N gave an 85% yield of silylated product at 25 °C
in DMF.10f Compound 4 was silylated in 99% and 73%
yield in acetonitrile and methylene chloride, respectively,
(15) Wroblewski, A. E.; Pinkas, K.; Verkade, J . G. Main Group
Chem. 1995, 1, 69.
(16) Verkade, J . G. Coord. Chem. Rev. 1994. 137, 233.
(17) Wilson, N. S.; Keay, B. A. Tetrahedron Lett. 1996, 37, 153.

5060 J . Org. Chem., Vol. 62, No. 15, 1997
D’Sa et al.
by our procedure using 1b. When the more hindered
nonionic base 1c was used as the catalyst for silylating
4 (Table 2) in methylene chloride, again a 73% yield of
the silylated product was obtained under the same
conditions, whereas a control reaction without catalyst
gave only a 30% yield of the silylated product (Table 2).
The reason for the lower yield of the silylated product of
4 using either 1a or 1c in methylene chloride compared
with acetonitrile is not clear.
We note in the present work that the acid-sensitive
alcohol 14, the base-sensitive alcohol 20, and a long-chain
alcohol as in the case of linoleoyl alcohol 17 were silylated
with TBDMSCl in high yields (Table 2). This table also
indicates that n-octyl alcohol 8 is cleanly silylated at room
temperature in acetonitrile, whereas under the same
conditions using TMG as a catalyst, this alcohol is
silylated in 93% yield.10a Secondary alcohols were sily-
lated to the corresponding TBDMS ethers in excellent
yields in less than 4 h in acetonitrile (Table 2). The
TBDMS silylation of alcohols 18 and 19 whether carried
out in the absence or presence of a solvent under the
same conditions gave similar yields of the silylated
products (Table 2).
From Tables 1 and 2 it is clear that our method is
compatibile with a variety of functional groups including
aldehydes, esters, nitriles, ketones, lactones, ethers, and
methylene-interrupted double bonds. It is observed from
these tables that, in general, a longer reaction time, a
higher catalyst concentration, a more polar solvent, and
a higher temperature lead to augmented yields of sily-
lated products. Recently Nelson and Crouch18 published
a review of selective deprotection schemes for a variety
of silyl ethers which should increase the use of TBDMS
and TBDPS protecting groups in organic synthesis. It
should be noted that TMSCl is dehydrohalogenated by
1b giving (Me2SiCH2)2,19 hence precluding the use of
TMSCl for alcohol silylation using our procedure.
Catalyst 1b has good solubility both in polar solvents
such as THF, diethyl ether, acetonitrile, pyridine, and
DMF and in nonpolar solvents such as pentane, benzene,
and hexane. Another advantage of 1b over conventional
silylation catalysts is that it is converted to crystalline
3b which is easily separated from the triethylammonium
hydrochloride and the silylated product formed in the
reaction. Because 3b is quite insoluble in nonpolar and
relatively weakly polar solvents such as diethyl ether,
ethyl acetate, pentane, and toluene, it can be easily
separated by filtration and recycled to 1b in a single step
using KO-t-Bu. To the best of our knowledge, no recovery
process for other silylation catalysts has been recorded.
This may be attributed to the considerable solubility of
the protonated forms of such catalysts in a variety of
solvents, thus inhibiting recycling efforts. For example,
protonated DBU salts are quite soluble in both polar as
well as nonpolar solvents.
of TBDMS ethers in cases where the use of DMF as a
solvent is not desirable or practical, (3) the catalyst can
be recycled in high yields, (4) the catalyst is compatible
with a variety of functional groups, (5) catalyst 1b is
commercially available (Strem Chemical Co.), and (6)
acid- and base-sensitive alcohols can be efficiently sily-
lated by our approach (see methods A and C in the
Experimental Section) because only 0.05 mL of water is
required for quenching 1b. Similar yields of silylated
alcohols can be obtained with or without a solvent. Minor
disadvantages of 1b are that it cannot be used for TMSCl
reactions or for the silylation of tertiary alcohols with
TBDPSCl.
Exp er im en ta l Section
Benzene and tetrahydrofuran were distilled from Na-
benzophenone, acetonitrile was distilled from calcium hydride,
triethylamine was distilled from potassium hydroxide, and
methylene chloride was distilled from P4O10. Anhydrous DMF,
TBDMSCl, TBDPSCl, dimethyl 3-oxoglutarate, 1-phenyl-1,2-
ethanediol, salicylic acid, and 2-amino-2-methyl-1-propanol
were purchased from Aldrich Chemical Co. and were used as
received. The bases 1b12 and 1c15 were prepared according to
our previously published method and were stored under
nitrogen. All reactions and distillations were carried out under
a nitrogen or argon atmosphere. The products were found to
1
be >97% pure by H NMR analysis.
Gen er a l P r ep a r a tive P r oced u r e for 1b-Ca ta lyzed Si-
lyla tion s of Alcoh ols. Meth od A. In a 100 mL flask was
dissolved a catalytic amount of 1b (Table 2) in 5.0 mL of dry
acetonitrile. To this was added 0.82 g (5.5 mmol) of TBDMSCl
followed by the addition of 0.76 mL (5.5 mmol) of Et3N. After
the mixture was stirred for 5 min, 5.0 mmol of the alcohol was
added with continued stirring at the temperature stated in
Table 2. After the stated reaction time in this table, 0.05 mL
of water was added with stirring. After evaporation of ∼95%
of the solvent under vacuum, 20 mL of ether was added and
stirring was continued for 5 min more to precipitate 3b as a
white solid. The mixture was filtered, and the residue was
washed with 2 × 5 mL of ether. The residue was collected for
subsequent recycling to 1b. The organic layer was dried with
anhydrous sodium sulfate followed by concentration under
vacuum to afford the crude silyl ether which was purified by
chromatography on silica gel using gradient elution. Thus
after the column was loaded with the crude silyl ether, the
polarity of the eluent was increased in steps of 5% using 50
mL of eluent in each step, starting from 50 mL of 100%
hexanes and ending with the ratio of the eluent indicated in
Table 2.
Meth od B. In a 100 mL flask was dissolved a catalytic
amount of 1b (Tables 1 and 2) in 3 mL of dry DMF under
nitrogen. After addition of 2.1 mmol of the silyl chloride,
followed by 0.29 mL (2.1 mmol) of Et3N, the mixture was
stirred for 5 min. Then 2.0 mmol of the alcohol was added
with continued stirring at the temperatures stated in Tables
1 and 2. After the stated reaction times in these tables, 5 mL
of water was added with stirring. This was followed by the
addition of 20 mL of ethyl acetate and stirring for 5 min more.
The organic layer was washed with 5 mL of aqueous saturated
sodium bicarbonate and then with 5 mL of water. After the
organic layer was dried over anhydrous sodium sulfate, the
mixture was filtered. The filtrate was concentrated under
vacuum at ∼40 °C affording the crude silyl ether which was
purified by chromatography on silica gel using gradient elution
as described in method A.
Con clu sion s
The nonionic superbase 1b is a superior catalyst for
alcohol and phenol protective silylations under mild
conditions using TBDMSCl and TBDPSCl. The advan-
tages of using 1b as a silylation catalyst are (1) the yields
of the silylated alcohols and phenols are high, (2) aceto-
nitrile or tetrahydrofuran can be used for the preparation
Meth od C. To a 100 mL flask containing a catalytic
amount of 1b (Table 2) was added 0.82 g (5.5 mmol) of
TBDMSCl followed by the addition of 0.76 mL (5.5 mmol) of
Et3N. After the mixture was stirred for 5 min, 5.0 mmol of
the alcohol was added with continued stirring at the temper-
ature stated in Table 2. After the reaction time stated in that
table, the mixture was diluted with 5 mL of acetonitrile. To
this was added 0.05 mL of water with stirring. The mixture
(18) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 9, 1031.
(19) Arumugam, S.; Verkade, J . G. To be published.

Nonionic Superbase-Catalyzed Silylation of Alcohols
J . Org. Chem., Vol. 62, No. 15, 1997 5061
was then filtered and the residue was washed with 2 × 5 mL
of ether. After evaporation of ∼95% of the solvent, 20 mL of
ether was added and stirring was continued for 5 min more
to precipitate 3b as a white solid. The mixture was then
filtered and the residue washed with 2 × 5 mL of ether. The
residue was dried under vacuum and saved for recycling to
1b. The organic layer was dried with anhydrous sodium
sulfate and filtered, and then the filtrate was concentrated
under vacuum, affording the crude silyl ether which was
purified by chromatography on silica gel using gradient elution
as described in method A.
Meth od D. In a 100 mL flask was dissolved 0.2 mmol of
the catalyst (Table 2) in 5 mL of dry methylene chloride. To
this was added 0.17 g (1.1 mmol) of TBDMSCl followed by the
addition of 0.15 mL (1.1 mmol) of Et3N. The mixture was
stirred for 5 min, after which 1.0 mmol of alcohol 4 was added
with continued stirring at 24 °C. After 3 h, 0.01 mL of water
was added with stirring. The mixture was filtered, the residue
was washed with 2 × 5 mL of ether, and then ∼95% of the
solvent was evaporated under vacuum. Ether (20 mL) was
added, and stirring was continued for 5 min more to precipitate
3b as a white solid. The mixture was filtered, and the residue
was washed with 2 × 5 mL of ether. The organic layer was
dried with anhydrous sodium sulfate and filtered, and then
the filtrate was concentrated under vacuum. The crude silyl
ether which remained was purified by chromatography on
silica gel using gradient elution as described in method A to
give 0.200 g (73%) of the silylated product.
was concentrated under vacuum, affording the crude dimethyl
3-hydroxyglutarate which was purified by chromatography on
silica gel using 65:35 hexanes:ethyl acetate as the eluent to
give 1.7 g of 21 in 72% yield after evaporation of the solvents.
The 1H NMR of the product compared favorably with that
reported in the literature.20
Recyclin g of 1b. The residues (∼4 g) obtained from
methods A and C were deprotonated using 1.4 equiv of KO-
t-Bu in 10 mL of acetonitrile in a Schlenk flask. The resulting
suspension was stirred overnight under nitrogen at 24 °C after
which the solvent was evaporated under vacuum at ∼40 °C.
Pentane (50 mL) was added, and the suspension was stirred
overnight under nitrogen. The clear pentane layer was
transferred to another Schlenk flask via a cannula or a syringe,
and then the solvent was evaporated under vacuum at 24 °C
to give a white solid which on sublimation (50 °C/100 mTorr)
gave pure 1b in ∼80% yield.
Ack n ow led gm en t. The authors thank the Center
for Advanced Technology Development of Iowa State
University and the donors of the Petroleum Research
Fund, administered by the American Chemical Society,
for grant support of this research.
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terizational data, NMR peak assignments, and 1H NMR
spectra (28 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
P r ep a r a tion of 21 fr om Dim eth yl 3-Oxoglu ta r a te. To
a 100 mL flask containing 2.0 mL (14 mmol) of dimethyl
3-oxoglutarate in 15 mL of methanol was added 0.24 g (6.8
mmol) of sodium borohydride in small portions over 5 min.
The reaction mixture was stirred for 1 h, and then 5 mL of
water was added. The aqueous layer was extracted with 2 ×
20 mL of ethyl acetate. The organic layer was dried with
anhydrous sodium sulfate and then it was filtered. The filtrate
J O9701492
(20) The Aldrich Library of 13C and 1H FT-NMR Spectra; Edition 1,
Volume 1, spectra no. 1043A
(21) Brown, H. C.; Ichikawa, K. Tetrahedron Lett. 1957, 1, 221.