Iodine-promoted silylation of alcohols with silyl chlorides. Synthetic and mechanistic studies

Article abstract of DOI:10.1016/j.tet.2008.06.070

An efficient silylating system for 1°, 2°, and 3° alcohols, consisting of a silyl chloride/N-methylimidazole/iodine, was developed. Synthetic and mechanistic aspects of this new reagent system, and particularly the role of iodine were investigated in detail using ¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tet.2008.06.070

Tetrahedron 64 (2008) 8843–8850
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Iodine-promoted silylation of alcohols with silyl chlorides. Synthetic
and mechanistic studies
,b,
Agnieszka Bartoszewicz a, Marcin Kalek a, Jacek Stawinski a
*
a Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden
b Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
An efficient silylating system for 1ꢀ, 2ꢀ, and 3ꢀ alcohols, consisting of a silyl chloride/N-methylimidazole/
iodine, was developed. Synthetic and mechanistic aspects of this new reagent system, and particularly
the role of iodine were investigated in detail using 1H NMR spectroscopy.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 30 April 2008
Received in revised form 2 June 2008
Accepted 19 June 2008
Available online 24 June 2008
1. Introduction
4-dimethylaminopyridine,14 or lithium sulfide15 as catalysts, have
been advocated for silylation of 1ꢀ and 2ꢀ alcohols.
Silyl ethers are among the most frequently used protective
groups for alcohols since both steric and electronic effects can
regulate the ease of their cleavage.1,2 For common trialkyl- and
alkylarylsilyl ethers, depending on substituents on the silicon atom,
differences in stability toward acids and bases span a range of 105
order of magnitude,3,4 and thus in multistep organic syntheses, two
or more different silyl protecting groups can be used simulta-
neously, and be removed selectively at different synthetic stages.1,4
Of particular importance is also the known lability of the silyl ethers
in the presence of fluoride ions, which provides a very convenient,
orthogonal way for their cleavage.4,5
Recently, during our studies on oxidative couplings of H-phos-
phonates with alcohols we observed, that relatively unreactive
silylating agent, tert-butyldiphenylsilyl chloride (TBDPS-Cl), exhibi-
ted enhanced reactivity toward alcohols in the presence of iodine.16
We found that the accelerating effect of iodine was not confined to
the TBDPS-Cl reagent, but was observed also for other silyl chlorides.
In this paper we report our detailed synthetic and mechanistic
investigations of this phenomenon, which led us to the
development of a new synthetic protocol for silylation of 1ꢀ, 2ꢀ, and
3ꢀ alcohols. A short account of this work has recently been
published as a communication.17
The most popular, by far, silylating agents are various trialkyl- or
alkylarylsilyl chlorides.6 However, since reactivity of silyl chlorides
toward alcohols is strongly affected by steric and electronic features
of substituents on the silicon atom, silyl esters that have syntheti-
cally useful stability are usually difficult to form, especially from 2ꢀ
and 3ꢀ alcohols. Thus, to facilitate introduction of silyl protecting
groups into hydroxylic compounds, a plethora of silylating agents
have been developed.4–7 Apart from the classical Corey–Ven-
kateswarlu reaction conditions (a silyl chloride with imidazole in
DMF),8 of particular importance are reagent systems that make use
of an increased reactivity of silyl chlorides in the presence of
various additives. One should mention here supersilylating
agents of type R3SiB(OTf)3Cl [formed from silyl chlorides and
B(OTf)3],9 or in situ generated silyl perchlorates or silyl nitrates.10,11
In addition, reagent systems consisting of silyl chlorides and
1,4-diazabicyclo[2.2.2]octane (DABCO),12 pyridine N-oxide,12
1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU),13 silver nitrate,10
2. Results and discussion
Preliminary experiments on silylation of nucleosides with
TBDMS-Cl in pyridine showed that the reactions were almost an
order of magnitude faster upon addition of iodine. To obtain some
insight into the role of iodine in these reactions, we investigated in
detail some chemical and mechanistic aspects of silylation of al-
cohols using silyl chlorides in the presence of iodine under various
experimental conditions.
Recently, a catalytic effect of iodine in conjunction with the
introduction of trimethylsilyl group using 1,1,1,3,3,3-hexame-
thyldisilazane (HMDS)18 or with silyl chlorides (TMS-Cl, TBDMS-Cl)
under microwave irradiation was reported,19 however, a mechanis-
tic role of iodine in these and in our systems, seems to be disparate.
2.1. Screening of the reaction conditions using 50- and 30-
protected thymidine derivatives and TBDMS-Cl
Two simple nucleoside derivatives, namely, 30-O-dimethoxy-
tritylthymidine (30-O-DMT-T,1) and 50-O-dimethoxytritylthymidine
* Corresponding author.
E-mail address: js@organ.su.se (J. Stawinski).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.06.070

8844
A. Bartoszewicz et al. / Tetrahedron 64 (2008) 8843–8850
(50-O-DMT-T, 2) (Scheme 1) were chosen as models for primary and
secondary alcohols, respectively. These were silylated in acetonitrile
with tert-butyldimethylsilyl chloride (TBDMS-Cl; 1.1 equiv) in the
presence of various bases and iodine. Progress of the reactions was
monitored by the TLC analysis, and the results are summarized in
Table 1.
dimethylaminopyridine (DMAP), imidazole, and N-methyl-
imidazole were used.
All these nucleophile catalysts were screened for their ability to
catalyze silylation of a model primary alcohol, namely, 30-O-DMT-T
(1) with TBDMS-Cl in different solvents, and in the presence of
variable amount of the added iodine (Table 2, the upper part). The
results obtained were in agreement with the already observed
trends in reactivity, irrespective of the solvent used (see, Table 1).
The accelerating effect of iodine was observed for the reactions
carried out in the presence of pyridine, DMAP, and N-methyl-
imidazole, but not for those with imidazole. DMAP, although ac-
O
N
O
N
NH
NH
TBDMS-Cl
(1.1 equiv)
catalyst + I2
HO
Si O
O
O
celerated the silylation reaction, it also exhibited
a similar
O
O
behavior to that observed for triethylamine and DIPEA (although
to smaller extent), and for this reason it was excluded from further
studies.
MeCN
ODMT
ODMT
1
For the silylation of a model secondary alcohol, 50-O-DMT-thy-
midine (2) (Table 2, lower part), the reaction times became longer,
but again a large rate enhancement was observed for the reactions
in which pyridine or N-methylimidazole was used together with
iodine. As for the reaction with 1, iodine had no effect on the rate of
silylation of nucleoside 2 in the presence of imidazole. All the re-
actions investigated were also rather insensitive to the nature of
the solvent used. Thus, it seemed that optimal reaction conditions
for silylation 1ꢀ and 2ꢀ with TBDMS-Cl, consisted of using N-
methylimidazole (3 equiv) as a nucleophile catalyst together with
iodine (2–3 equiv) in THF or acetonitrile.
O
N
O
N
NH
NH
TBDMS-Cl
(1.1 equiv)
catalyst + I2
DMTO
DMTO
O
O
O
O
MeCN
OH
O
Si
2
DMT = 4,4'-dimethoxytrityl
TBDMS-Cl = t-butyldimethylsilyl chloride
Scheme 1. Silylation of nucleoside derivatives as models for 1ꢀ (1) and 2ꢀ (2) alcohols.
As it was apparent from data in Table 1, iodine indeed efficiently
accelerated the silylation when the reaction was carried out in the
presence of pyridine and N-methylimidazole, but no catalytic effect
was observed for the reactions in which imidazole was used. Ter-
tiary amines, such as triethylamine (Et3N) or diisopropylethylamine
(i-Pr2NEt), only negligibly speed up the silylation. In addition, these
amines turned out to be incompatible with iodine, apparently due
to a rapid reaction20 that led to a complete consumption of the
amine and iodine. No silylation of nucleosides 1 and 2 could be
observed when 2,6-lutidine alone, or in combination with iodine,
was used for the reaction.
These experiments indicated that base catalysis during silyla-
tion of alcohols with silyl chlorides was rather inefficient, and that
an amine, which was also used as an acid scavenger, had to have
nucleophilic properties to accelerate the reaction. Somewhat puz-
zling, however, was the fact that silylation reactions in which im-
idazole was used were insensitive to the addition of iodine (vide
infra). The lack of detectable silylation in the reaction in the pres-
ence of 2,6-lutidine indicated that iodine alone did not have any
catalytic activity in the reactions investigated.
2.2. Silylation of nucleoside 2 with different silyl chlorides
After having established the optimal reaction conditions for
silylation of primary and secondary alcohols with TBDMS-Cl (vide
supra), we investigated also other silyl chlorides that were fre-
quently used for the protection of alcohols in organic synthesis. The
silylation experiments were carried out using the less reactive 2ꢀ
alcohol, namely 50-O-DMT-T (2), and different silyl chlorides. Data
in Table 3 show the reaction times for silylations of 2 under stan-
dard Corey–Venkateswarlu conditions,8 and those for the reactions
in which N-methylimidazole was used alone, or in combination
with iodine.
For the silyl chlorides with three unbranched alkyl chains (TMS-
Cl, TES-Cl, and TPS-Cl), the silylationwas fast (ca. 5 min), irrespective
of the reaction conditions used. More pronounced differences,
however, became visible for bulky silylating agents. Moderately
sterically hindered silyl chlorides, e.g., TBDMS-Cl, TDS-Cl, and
TBDPS-Cl, reacted significantly slower than simple trialkylsilane
derivatives, and in all instances the best results were obtained when
N-methylimidazole/iodine reagent system was used. The effect of
iodine on the rate of silylation was particularly pronounced for
TBDPS-Cl, for which the reaction time could be shortened from 5 h
to 10 min.
Since the accelerating effect of iodine on silylation of alcohols
seemed to be connected to the presence of nucleophilic catalysts in
the reaction mixture, in our further studies only pyridine,
For the most sterically hindered silyl chloride investigated, TIPS-
Cl, silylation of 2ꢀ hydroxyl group in 2 was rather slow, and even in
the presence of iodine, the reaction went only to 40% completion
after 8 h.
Table 1
Reaction times for the silylation of 1 and 2 in acetonitrile under different experi-
mental conditions
Base
Reaction time for 1
Reaction time for 2
(2.2 equiv)
(conversion, if not 100%)
(conversion, if not 100%)
2.3. Mechanistic studies on the role of iodine in the
investigated reactions
No I2
5 equiv I2
No I2
5 equiv I2
Pyridine
6 h
30 min
10 min
3 h (w10%)
3 h (w10%)
No reaction
45 min
2 min
No reaction
6 h
4 h
No reaction
No reaction
No reaction
6 h (w30%)
1 h
N-Methylimidazole
Imidazole
Et3N
i-Pr2NEt
2,6-Lutidine
Although a catalytic effect of iodine during silylation was
reported for 1,1,1,3,3,3-hexamethyldisilazane (HMDS)18 and for
some silyl chlorides (TMS-Cl, TBDMS-Cl) under microwave irradi-
ation,19 a mechanistic role of iodine remained elusive. One should
note, that those reactions were carried out with sub-stoichiometric
amounts of iodine and without nucleophile catalysts and thus,
most likely, different mechanisms operated than that in our sily-
lation reactions.
10 min
nda
4 h
No reactionb
No reactionb
No reaction
nda
No reaction
a
Not determined due to side reaction of iodine with trialkylamines, leading to
detritylation of the starting material and the products.
b
Similar behavior as described above in footnote a was observed, however no
products were formed at any time.

A. Bartoszewicz et al. / Tetrahedron 64 (2008) 8843–8850
8845
Table 2
The reaction times for silylation of 1 and 2 with TBDMS-Cl, using different nucleophile catalysts, solvents, and various amounts of the added iodine
Nucleophile catalyst (2.2 equiv)
Solvent
Reaction times for silylation of 1ꢀ alcohol 1 (conversion, if not 100%)
No I2
1 equiv I2
3 equiv I2
5 equiv I2
Pyridine
Pyridine
Neat
CH3CN
5 h
6 h
3 h
5 h
45 min
1 h
45 min
45 min
DMAP
DMAP
Pyridine
CH3CN
5 h
15 min (w30%)
3 h (w70%)a
15 min (w60%)
1 h (w70%)b
45 min
45 min
1 h (60%)
15 min (w60%)
1 h (w70%)b
15 min (w60%)
1 h (w70%)b
Imidazole
Imidazole
Imidazole
Imidazole
Pyridine
CH3CN
DMF
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
10 min
THF
N-Methylimidazole
N-Methylimidazole
N-Methylimidazole
Pyridine
CH3CN
THF
30 min
30 min
30 min
5 min
5 min
5 min
2 min
2 min
2 min
2 min
2 min
2 min
Nucleophile catalyst (2.2 equiv)
Solvent
Reaction times for silylation of 2ꢀ alcohol 2 (conversion, if not 100%)
No I2
1 equiv I2
3 equiv I2
5 equiv I2
Pyridine
Pyridine
Neat
CH3CN
5 h (w5%)
No
5 h (w20%)
6 h (w5%)
5 h (w50%)
6 h (w20%)
5 h (w80%)
6 h (w30%)
reaction
Imidazole
Imidazole
Imidazole
Imidazole
Pyridine
CH3CN
DMF
5 h
4 h
4 h
4 h
5 h
4 h
4 h
4 h
5 h
4 h
4 h
4 h
5 h
4 h
4 h
4 h
THF
N-Methylimidazole
N-Methylimidazole
N-Methylimidazole
Pyridine
CH3CN
THF
5 h
6 h
6 h
1.5 h
2 h
1.5 h
1 h
1 h
1 h
1 h
1 h
1 h
a
DMAP seemed to react with iodine similarly to Et3N and DIPEA, but slower and led incomplete reactions.
Due to consumption of base in the reaction of DMAP with iodine, the detritylation was observed after prolonged reaction time (1 h).
b
Analysis of data from Tables 1 and 2 seemed to suggest that
a reaction of a silyl chloride with a nucleophile catalyst to form
a reactive intermediate A, from which, upon the reaction with an
alcohol, a silyl ether was formed. Assuming the known propensity
of iodine to catenation and formation of polyhalide anions,22 it was
likely that in the presence of iodine the concentration of chloride
anions, generated in the first reaction step, could be depleted due to
formation of less nucleophilic anions I2Cl–. Thus, for the
investigated silylation reaction, the equilibrium between a silyl
chloride and a nucleophile catalyst could be shifted toward adduct
A, the most likely reactive intermediate in these reactions.
Consistent with this interpretation was the fact that the accel-
erating effect of iodine was always proportional to the amount of
iodine used for the reaction, and that a nucleophile catalyst was an
indispensable component of the reaction mixtures.
To substantiate the proposed mechanism for the enhanced ki-
netic of silylation of alcohols by iodine, we carried out some NMR
experiments. We wanted to find out if silyl-nucleophile catalyst
adducts of type A could be detected by 1H NMR spectroscopy in the
a mechanistic role of iodine in our reactions might be related to
that ascribed to iodine in certain phosphorylation reactions,16,21
and a plausible mechanism was depicted in Scheme 2. It involved
Table 3
Comparison of the reaction times for silylation of nucleoside 2 using different silyl
chlorides
Silyl
Formula
Reaction times for silylation of nucleoside 2
chloride
(conversion, if not 100%)
Imidazole
N-Methyl-
N-Methyl-
(3 equiv, DMF) imidazole
imidazoleþI2
(3 equiv, THF) (both 3 equiv, THF)
TMS-Cl
TES-Cl
5 min
5 min
5 min
5 min
5 min
5 min
Si Cl
Si Cl
R1
TPS-Cl
5 min
4 h
5 min
6 h
5 min
1 h
Si Cl
Si Cl
Si Cl
R2 Si OR4
R3
TBDMS-Cl
TDS-Cl
R4OH
R1
R2 Si Cl
R3
R1
8 h
(w40%)
6 h
1 h
I2
R2 Si Nu
I2Cl-
+
+
Cl-
Nu
R3
A
Ph
Si Cl
Ph
8 h
(w40%)
TBDPS-Cl
TIPS-Cl
5 h
10 min
or
or
Nu =
N
N
N
N
N
R1, R2, R3 = alkyl or aryl groups
8 h
(w40%)
8 h
(w10%)
8 h
(w40%)
Si Cl
Scheme 2. A putative mechanism of silylation of alcohols in the presence of iodine and
a nucleophile catalyst.

8846
A. Bartoszewicz et al. / Tetrahedron 64 (2008) 8843–8850
Table 4
Formation of TBDMS-nucleophile catalyst adducts in the absence and in the presence of iodinea
Silyl substrate
Additives
Nucleophile catalyst
Imidazole
Pyridine
Si N
(CH ) Si = 0.54
N-Methylimidazole
N
N
Si N
Si N
(CH ) Si = 0.54
(CH ) Si = 0.61
3
2
3 2
3
2
(CH ) C = 0.98
(CH ) C = 0.93
(CH ) C = 0.94
3
3
3 3
3
3
% of the adduct formedb
60
3 equiv nucleophile catalyst
0
0
0
Si Cl
(CH ) Si = 0.34
3
2
3 equiv nucleophile catalystþ3 equiv iodine
52
32, d(CH ) Si¼0.71,c
3
2
(CH ) C = 0.96
3
3
d(CH ) C¼1.01
3
3
Si OTf
(CH ) Si = 0.46
3 equiv nucleophile catalyst
100
100
100
3
2
(CH ) C = 1.00
3
3
a
b
c
TBDMS-X (0.066 M), 0.20 M nucleophile catalyst (0.20 M I2), in CDCl3.
Percentage of the adduct was calculated by integration of the corresponding (CH3)2Si signals.
Chemical shifts of the signals from the N-methyl-N0-TBDMS-imidazolium adduct generated from TBDMS-Cl slightly differed from those when TBDMS-OTf was used as the
substrate; we believe that these differences were due to different kind of counterions present (Clꢁ vs OTfꢁ).
reaction mixtures, and if there was a relationship between their
concentrations and the observed rates of the silylations. We also
hoped that these experiments would clarify the issues why the
accelerating effect of iodine was not observed for the reactions with
silyl chlorides, when imidazole was used as a nucleophile catalyst.
Another picture emerged when imidazole was added to TBDMS-
Cl in chloroform. In this instance two sets of resonances, assigned to
TBDMS-Cl and to the corresponding N-silylimidazole (60%), could
be discerned in the 1H NMR spectrum. The later species was formed
quantitatively upon the reaction of TBDMS-OTf with imidazole. An
interesting observation was that addition of iodine to the reaction
mixture containing this N-silylimidazole intermediate, did not
increase its concentration, but slightly lowered it.
2.4. 1H NMR studies on the mechanism of silylation in
the presence of iodine
The reaction with N-methylimidazole with TBDMS-Cl did not
produce detectable amounts of the putative N-methyl-N0-TBDMS-
imidazolium adduct, however, the addition of iodine (3 equiv) to
such reaction mixture resulted in an immediate formation of the
expected species (32%). Similarly, as it was observed for other nu-
cleophile catalysts, addition of N-methylimidazole to TBDMS-OTf,
caused a quantitative formation of the N-methyl-N0-TBDMS-imi-
dazolium adduct. To prove chemical identity of the adduct formed,
the NMR sample was subjected to a mass spectrometry analysis
(ESI), which indeed showed the presence of the expected mass
peak (m/z 197.1470 [M]þ, C10H21N2Siþ calcd 197.1469) corre-
sponding to the N-methyl-N0-TBDMS-imidazolium adduct. Addi-
tionally, the mass spectra registered in the negative mode showed
a strong signal (m/z 288) corresponding to I2Cl–.
A similar series of experiments were performed for trime-
thylsilyl derivatives (TMS-X). In addition to TMS-Cl and TMS-OTf,
commercially available TMS-Br was included into this study (Table
5). By using TMS-Br we were able to observe the effect of the iodine
addition on building up the concentration of the N-TMS-pyridinium
adduct, from null to 100%. Since the same intermediate was also
formed from TMS-OTf, and had a chemical shift identical to that of
a reference compound produced on another way,24 we believe that
the signals assigned to the N-silylpyridinium adducts in our
experiments, corresponded to distinct chemical species, rather
than to a weighted average of two equilibrating species.
NMR spectroscopy is a convenient tool to directly observe re-
active intermediates involved in various equilibria, if life-times of
the species involved are long enough on the NMR timescale for
a given observed nuclei. If the intermediates are short lived, then
instead of separate sets of signals originating from these species,
only time average NMR parameters (chemical shifts and coupling
constants) are accessible from the spectra.
In these studies, we wanted to determine positions of equilibria
between various silyl chlorides and their adducts with nucleophile
catalysts, and to find out how these equilibria were affected upon
addition of iodine to the reaction mixtures.
For the silyl ethers investigated, convenient diagnostic signals in
the 1H NMR spectra were those from the CH3 groups bound directly
to the silicon atom, and from the t-butyl group of a TBDMS moiety.
These signals, which chemical shifts changed upon the adducts
formations, appeared in the otherwise empty region of the 1H NMR
spectra (ca. 0–1 ppm) and could be easily integrated for the pur-
pose of quantitative analysis.
Table 4 summarized the 1H NMR experiments, in which TBDMS
adducts bearing different nucleophile catalysts moieties were
generated in CDCl3 from TBDMS-Cl and TBDMS-OTf.
For TBDMS-Cl in the presence of pyridine, or pyridine and
iodine, in the 1H NMR spectra only signals due to the silyl chloride
could be detected. These indicated, that the corresponding silyl-
pyridinium adduct was apparently formed only in a minute
amount, even in the presence of iodine. In contrast to this, addition
of pyridine (3 equiv) to a chloroform solution of TBDMS-OTf
resulted in an immediate disappearance of the signals of the
starting material, and formation of two resonances at the high-field
In contrast to pyridine, imidazole produced the N-TMS-imid-
azole intermediate quantitatively from all three silyl precursors. For
N-methylimidazole, however, the N-methyl-N0-TMS-imidazolium
adduct was formed from TMS-Cl only in presence of iodine.
Although these results, together with data from Tables 1 and 2,
indicated the kinetic importance of the increasing concentration of
silyl-nucleophile adduct intermediates by the added iodine, we
(
dH¼0.54 and 0.98 ppm; ratio 9:6), assigned to two different types
of the methyl groups in the N-silylpyridinium intermediate.23

A. Bartoszewicz et al. / Tetrahedron 64 (2008) 8843–8850
8847
Table 5
Formation of TMS-nucleophile catalyst adducts in the absence and in the presence of iodinea
Silyl substrate
Additives
Nucleophile catalyst
Imidazole
Pyridine
N-Methylimidazole
N
N
Si N
Si N
Si N
(CH ) Si = 0.72
(CH ) Si = 0.48
(CH ) Si = 0.59
3
3
3 3
3
3
% of the adduct formedb
100
3 equiv nucleophile catalyst
0
0
Si Cl
(CH ) Si = 0.44
3
3
3 equiv nucleophile catalystþ3 equiv iodine
0
0
100
100
100
ndc
3 equiv nucleophile catalyst
Si Br
(CH ) Si = 0.59
3 equiv nucleophile catalystþ3 equiv iodine
100
100
100
100
ndc
3
3
Si OTf
3 equiv nucleophile catalyst
100
(CH ) Si = 0.51
3
3
a
b
c
TMS-X (0.066 M), 0.20 M nucleophile catalyst (0.20 M I2), in CDCl3.
Percentage of the adduct was calculated by integration of the corresponding (CH3)3Si signals.
Not determined, due to identical chemical shifts of the signals from TMS-Br and N-methyl-N0-TMS-imidazolium adduct (0.59 ppm).
additionally performed 1H NMR titration experiments of the re-
action mixtures containing TBDMS-Cl and imidazole or N-methyl-
imidazole, with iodine in different solvents.
The titration data are shown in Figures 1 and 2. For the reactions
with imidazole (Fig. 1), most of the silylating agent was trans-
formed into the adduct (w60% in CDCl3 and w75% in CD3CN) even
without iodine, and the addition of iodine had only a minor effect
on the adduct concentration in both solvents.
A completely different picture emerged when a nucleophile
catalyst was changed to N-methylimidazole (Fig. 2). Without io-
dine, in all solvents investigated, there was no detectable formation
of the N-methyl-N0-TBDMS-imidazolium adduct. However, with the
increasing amounts of the added iodine, the adduct concentration
was gradually built-up, and its concentration strongly depended on
solvent polarity. In less polar CDCl3 and THF concentration of the
adduct reached approximately 30%, whereas in more polar aceto-
nitrile, the adduct formation was almost quantitative in the pres-
ence of >3 equiv of iodine.
The above 1H NMR experiments provided a strong support for
the mechanism depicted in Scheme 2, explaining the accelerating
effect of iodine during silylation of alcohols using silyl chlorides in
the presence of nucleophile catalysts.
For the reactions investigated, crucial factors seemed to be the
intrinsic reactivity of a silyl-nucleophile adduct formed and its
concentration in the reaction mixture. An equilibrium concentra-
tion of the adduct of type A (Scheme 2), generated under the
reaction conditions from a silyl chloride and a nucleophile catalyst,
depended on its reactivity, and was the smallest for the most
reactive adducts. The added iodine could apparently change this
situation, and by complexing chloride anions, made the equilibrium
more favorable, i.e., to shift it toward the adduct formation.
N-Silylpyridinium adducts seemed to be the most reactive ones
among the species investigated, and thus their concentration was
extremely low, in the presence of nucleophilic anions such as chlo-
rides or bromides. The addition of iodine apparently increased the
equilibrium concentration of the silyl-pyridine adduct (although it
Figure 2. Titration of 0.066 M TBDMS-Cl and 0.20 M N-methylimidazole (3 equiv)
with I2. The presence of N-methylimidazole seemed to increase solubility of iodine, so
in this case the solubility limit was reached at approx. 3.5 equiv I2 in all three solvents.
Percentage of the adduct was calculated from the integration of (CH3)2Si signals of
TBDMS-Cl and the adduct.
Figure 1. Titration of 0.066 M TBDMS-Cl and 0.20 M imidazole (3 equiv) with I2, in
CD3CN and CDCl3. Under these conditions maximum solubility of I2 in CDCl3 was
reached at w1.5 equiv. Percentage of the adduct was calculated from integration of the
(CH3)2Si signals from TBDMS-Cl and the adduct.

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A. Bartoszewicz et al. / Tetrahedron 64 (2008) 8843–8850
Table 6
Examples of silylation of various alcohols using silyl chlorides/N-methylimidazole/iodine reagent systems
Entry
Alcohol
Product
Isolated yield (%)
Reaction time
Solvent/comments
1
2
89
93
5 min
5 min
CH2Cl2
CH2Cl2
OH
OH
OTIPS
OTBDPS
H2N
H2N
3
4
98
86
5 h
THF
THF
OH
OH
Ph
OTBDPS
OTBDPS
Ph
10 min
Ph
Ph
H
H
H
5
6
96
98
1 h
THF
THF
H
H
H
HO
TBDMSO
O
O
NH
NH
1 h
N
O
N
O
DMTO
DMTO
DMTO
O
O
OH
OTBDMS
O
O
N
NH
NH
O
N
O
O
DMTO
O
7
8
96
80
15 min
THF
OH NH2
O
TBDPSO
NH2
O
6 h
CH2Cl2
CH2Cl2
TBDMSO
TBDMSO
HO
HO
9
95
85
5 min
16 h
OH
OTBDPS
calc¼0.4 M neat N-methyl-
10
imidazole 6 equiv I2
11
82
1 h
THF
TBDMSO
OTBDPS
HO
OH
12
13
98
94
10 min
10 min
THF
THF
HO
OH
O
TBDMSO
OTBDMS
OTBDMS
OH
O
O
O
O
O
O
14
94
15 min
THF
O
O
O

A. Bartoszewicz et al. / Tetrahedron 64 (2008) 8843–8850
8849
Table 7
Silylation of polyhydroxy alcohols using a silyl chloride/N-methylimidazole/iodine reagent system
Entry
Alcohol
Product
Isolated yield (%)
Reaction time (min)
Comments
O
O
N
NH
NH
N
O
O
TBDMSO
HO
O
O
1
72
10
Pyridine
OH
OH
HO
HO
TBDMSO
HO
O
O
2
3
86
96
10
5
CH2Cl2
CH2Cl2
HO
HO
OH
OH
O
O
OH
OH
OTDS
OH
remained below the detection level of 1H NMR spectroscopy), and
this accelerated silylation of alcohols up to 5–6 times.
The efficacy of this new reagent system was assessed by carrying
out silylation of 1ꢀ, 2ꢀ, and 3ꢀ alcohols with diverse structural fea-
tures (simple alkyls, allylic, propargyl, and benzyl derivatives,
cholesteryl, nucleoside derivatives, protected carbohydrates) and
by using different silylating agents (TBDMS-Cl, TIPS-Cl, and TBDPS-
Cl; Table 6). The silylation of primary alcohols was always rapid (ca.
5–10 min; entries 1, 2, 9, and 13), irrespective of the kind of the silyl
chloride used (TBDMS-Cl, TBDPS-Cl, and TIPS-Cl). For secondary
alcohols, a typical reaction time for the silylation was ca. 15–60 min
(entries 4–7, 12, and 14) and only for 2ꢀ alcohols with a high steric
hindrance (entry 3), or with special chemical features (entry 8;
a ketone-ketal equilibrium), the reaction took longer time (ca. 5 h).
Very unreactive tertiary alcohol, 1-adamantanol (entry 10), could
also be silylated in high yield, but the reaction had to be performed
in neat N-methylimidazole in the presence of 6 equiv of iodine. On
average, the reactions in Table 1 were 5–30 times faster than those
without iodine performed under the standard Corey–Ven-
kateswarlu silylation conditions, using silyl chloride and imidazole
in DMF.8,17 The accelerating effect of the added iodine was largest
for the slowest reactions and in the extreme case (entry 10), the
silylation could only be carried under the new reaction conditions.
Although a silyl chloride/N-methylimidazole/iodine reagent sys-
tem tolerated various functional groups present in the substrates
(Table 6), these reaction conditions were incompatible with thiols
(oxidation to disulfides in the presence of iodine), terminal acetylenic
bonds (iodination) and certain electron-rich phenols (iodination in
the aromatic ring; see the Supplementary data for more details).
The highest accelerating effect of iodine was observed for the
reactions in which N-methylimidazole was used as a nucleophile
catalyst. This was consistent with data in Table 4 that showed that
without iodine, there was no detectable formation of the putative
reactive intermediate, the TBDMS-N-methylimidazolium adduct,
but the addition of iodine, increased its concentration to ca. 32%.25
The lack of an accelerating effect of iodine in the silylation
reactions in which imidazole was used as a acid scavenger and
a nucleophile catalyst, became apparent from analysis of data in
Tables 4 and 5. In these reactions, the reactive intermediates, i.e.,
the corresponding, electrically neutral, N-silylimidazole derivatives
were formed in high concentrations (60–100%), even without
iodine. For this reason, no accelerating effect of the added iodine
could be observed for the silylation reactions involving the
intermediacy of these species.
One should bear in mind that a nucleophile catalyzed silyla-
tion of alcohols, as that shown in Scheme 2, involved two reaction
steps: generation of a reactive intermediate of type A, and its
reaction with an alcohol. Depending on reactivity of a silyl chlo-
ride and a nucleophile catalyst used, the first or the second step
could be a rate-determining one, or both steps, could be kineti-
cally important. For the most reactive silyl chlorides (e.g., TMS-Cl
or other simple trialkylsilyl chlorides), apparently the formation
of reactive intermediates (silyl-nucleophile catalyst adducts) was
a rate-determining step, and thus the silylation reactions should
not be affected by the added iodine (Tables 3 and 5). For the less
reactive silyl chlorides (e.g., TBDMS-Cl or TBDPS-Cl), apparently
2.6. Regioselectivitydsilylation of diols and polyols
a
steady state kinetic applied, and thus the equilibrium
between a silyl chloride and a nucleophile catalyst, which could
be affected by the added iodine, became kinetically significant
(Tables 3 and 4).
Three hydroxylic compounds, namely, thymidine, 1-O-methyl-
glucopyranose, and a 1,3-diol were selected to verify regiose-
lectivity of the silylation under the new reaction conditions.
As it was apparent from data in Table 7, for all compounds in-
vestigated it was possible to efficiently introduce the silyl group
(TBDMS, entries 1 and 2; and TDS, entry 3) on the primary hydroxyl
function. Since these data are comparable to those for the reactions
without iodine, it seems that a silyl chloride/NMeIm/iodine reagent
system does not compromise noticeably regioselectivity of the
silylation.
2.5. Synthetic examples of silylation of alcohols using silyl
chlorides/N-methylimidazole/iodine reagent systems
Based on the above discussed model experiments and mecha-
nistic studies, we arrived to an efficient synthetic protocol for
silylation of alcohols. This consisted of using solvents convenient to
work with (e.g., THF, acetonitrile, or methylene chloride, depending
on solubility of substrates), N-methylimidazole (3 equiv) as a base
and a nucleophile catalyst, and iodine (2–3 equiv). Concentration of
alcohols was kept between 0.2 and 0.4 M, to ensure smooth and fast
silylation at room temperature.
3. Conclusions
An efficient protocol for silylation of 1ꢀ, 2ꢀ, and 3ꢀ alcohols,
consisting of using
a silyl chloride in the presence of N-

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A. Bartoszewicz et al. / Tetrahedron 64 (2008) 8843–8850
methylimidazole and iodine, was developed. The reactions can be
carried out in various organic solvents (e.g., THF, acetonitrile,
methylene chloride, and pyridine), at room temperature, and are
compatible with the presence of common functional groups. The
procedure is experimentally simple, high yielding, and expands
range of synthetic methods available for silylation of complex or-
ganic compounds. Application of N-methylimidazole together with
iodine resulted in significant shortening of the silylation time, both
for primary and secondary alcohols. The silylation occurred 5–30
times faster than that under standard conditions when imidazole
was used as a nucleophile catalyst and DMF as a solvent. The re-
action pathway was studied in depth and a mechanistic role of
iodine was elucidated by 1H NMR spectroscopy. It was found that
a base used for the reaction had to have nucleophilic properties,
and that iodine increased concentration of a reactive silyl-nucleo-
phile adduct in the reaction mixture.
chromatography (CH2Cl2/MeOH 100:0/95:5, Table 6 entries 1, 3,
and 7; pentane/AcOEt 10:0/9:1, Table 6 entries 2, 4–6, and 8–
14). The synthesized compounds were fully characterized by 1H
and 13C NMR spectroscopies and HRMS analysis (see the Sup-
plementary data for details).
Acknowledgements
Financial support from the Swedish Research Council is grate-
fully acknowledged.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.06.070.
4. Experimental part
4.1. General
References and notes
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Kocienski, P. J., Ed.; Thieme: Stuttgart, 2004.
All reagents were commercial grades and were used without
further purification.
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4778.
Acetonitrile, deuterated acetonitrile, DMF, deuterated chloro-
form, and N-methylimidazole were dried over activated molecular
sieves 4 Å. Pyridine was distilled from CaH2 and stored over mo-
lecular sieves 4 Å. THF was distilled directly before the use from
sodium/benzophenone. CH2Cl2 was distilled directly before the use
from P2O5.
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Tully, C. R. J. Org. Chem. 1978, 43, 3649–3653.
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H. Bull. Chem. Soc. Jpn. 1985, 58, 3669–3670.
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Progress of the reactions was monitored by thin layer chro-
matography (TLC) using silica gel-coated plates with a fluores-
cent indicator (Merck, Silica gel 60). Column chromatography
was performed on silica gel (Grace Davison, Davsil, 0.035–
0.070 mm). After chromatography, the fractions containing the
desired products were pooled, evaporated, and dried under
vacuum for 12 h. 1H and 13C NMR spectra were recorded on
Bruker Avance 400 MHz and 500 MHz instruments. Chemical
shifts are reported in parts per million, relative to TMS. As-
signment of the NMR signals was done on the basis of 2D
correlation experiments (COSY, HSQC, and HMBC) and NOEDiff.
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MicrOTOF ESI-TOF mass spectrometer.
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4.2. A general procedure for preparative silylation of alcohols
listed in Table 6
23. Since we did not observe simultaneously signals from the TBDMS-OTf and
those of the corresponding silylpyridinium intermediate, we could not exclude
a possibility that these two species existed in a rapid equilibrium. However,
since the observed signals were sifted significantly to the high field, the pos-
tulated adduct probably was formed in large amount.
An alcohol (1.0 mmol), N-methylimidazole (3.0 mmol), and
iodine (2.0–3.0 mmol) were dissolved in an appropriate, anhy-
drous solvent (3 mL, Table 6), and to these, a silyl chloride
(1.1 mmol) was added. The reaction mixture was stirred at room
temperature until complete disappearance of the starting mate-
rial (TLC analysis). The solvent was then evaporated, the residue
dissolved in ethyl acetate and washed with concd aqueous
Na2S2O3. The organic phase was dried over anhydrous Na2SO4
and evaporated. The products were purified by silica gel column
24. Olah, G. A.; Klumpp, D. A. Synthesis 1997, 744–746.
25. The reaction times for silylation of nucleosides 1 and 2 in the presence of
N-methylimidazole and I2 in THF and in acetonitrile in Table 2 are practically
the same despite significant differences in concentrations of the reactive in-
termediate generated in these two solvents. A probably reason for this behavior
can be rather poor solubility of the nucleosides in acetonitrile (heterogeneous
reaction), comparing to a very good solubility in THF, what could slow down
the silylation rate in the former solvent.