38
A. Bartoszewicz et al.
LETTER
When carried out in the presence of N-methylimidazole As to the mechanistic role of iodine in the investigated re-
(2.2 equiv), instead of pyridine, the analogous silylation actions (Scheme 2), we believe that it is related to that as-
reactions were significantly faster, and went to comple- cribed to iodine in certain phosphorylation reactions,12 for
tion within 30 minutes, irrespective of solvent used which a tentative mechanism has been proposed.8 Assum-
(Scheme 1). Addition of iodine (1 equiv) to the reaction ing the known propensity of iodine to catenation and for-
mixtures in THF, acetonitrile or pyridine, decreased the mation of polyhalide anions,13 it is likely that in the
reaction time to five minutes. With the more iodine (3 presence of iodine the concentration of chloride anions in
equiv) added, the silylation proceeded even faster (ca. 2 the reaction mixtures can be depleted due to formation of
min for the completion), but the rates did not increase fur- less nucleophilic anions I2Cl–. Because of this, the equilib-
ther with higher excess of iodine (5 equiv).
rium between a silyl chloride and a nucleophile catalyst
will be shifted towards adduct A, the most likely reactive
intermediate in the silylation reactions (Scheme 2). Con-
sistent with this interpretation was the fact that the catalyt-
ic effect was always proportional to the amount of iodine
used for the reaction, and that a nucleophilic catalyst was
an indispensable component of the reaction mixtures in
order to observe the catalytic effect of iodine.
A similar set of experiments was carried out on 5¢-O-
dimethoxytritylthymidine (entry 1, Table 1) as a model
compound for secondary hydroxyl functions, which are
known to undergo silylation with more difficulty than pri-
mary alcohols. Indeed, in acetonitrile in the presence of
pyridine (2.2 equiv), the silylation with TBDMSCl did not
occur at all (5 h), and in neat pyridine it proceeded very
slowly (ca. 5% after 5 h). The addition of iodine sped To substantiate the proposed mechanism of iodine action,
1
these reactions up (ca. 30% and 80% silylation, respec- some NMR experiments were carried out. The H NMR
tively, after 5 h), but the reaction did not go to completion. spectra of TBDMSCl in CDCl3 displayed two singlets at
In contrast, the silylation in THF in the presence of d = 0.96 and 0.34 ppm, assigned to the tert-butyl and the
N-methylimidazole (2.2 equiv) and iodine (3 equiv) af- methyl protons, respectively. The addition of N-meth-
forded quantitatively the desired 3¢-O-silylated nucleoside ylimidazole (3 equiv) or iodine (3 equiv) did not result in
within one hour vs. five hours for the reaction in the ab- any changes in this region of the spectrum. However,
sence of iodine.
when these two reagents (N-methylimidazole and iodine)
were added together to the reaction mixture, two addition-
al singlets at d = 1.01 and 0.71 ppm appeared. The chem-
ical shifts and the relative integrals (3:2, respectively) of
the signals suggested that they originated from tert-bu-
tyldimethylsilyl group in a new species (presumably ad-
duct A, ca 32%, Scheme 2). To prove the chemical
identity of the intermediate formed, the NMR sample was
subjected to mass spectrometry analysis (ESI), which in-
deed showed the presence of the expected mass peak (m/z
[M]+ calcd for C10H21N2Si+: 197.1469; found: 197.1470)
corresponding to the adduct A. Additionally, the mass
spectra registered in the negative mode showed a strong
signal (m/z = 288) corresponding to I2Cl–.
On the basis of these model experiments we formulated a
synthetic protocol for the silylation of alcohols, consisting
of THF, acetonitrile or CH2Cl2 as a solvent (depending on
solubility of substrates), N-methylimidazole (3 equiv) as
the base and a nucleophilic catalyst, and iodine (2–3
equiv).11
The efficacy of this new reagent system was assessed by
carrying out silylation of alcohols with diverse structural
features and by using different silylating agents (Table 1).
The silylation of primary alcohols was always rapid (ca. 5
min; entries 2, 3, and 9), irrespective of the kind of the si-
lylating agent used (TBDMSCl, TBDPSCl, TIPSCl). For
secondary alcohols, a typical reaction time for the silyla-
tion was ca. 15–60 min (entries 1, 5, 6, 7) and only for sec-
ondary alcohols with high steric hindrance (entry 4) or
with special chemical features (entry 8; a ketone–ketal
These preliminary results strongly support the proposed
mechanism for the catalytic role of iodine in our reagent
system.
equilibrium), did the reaction take longer time (ca. 5 h). It should be noted that other studies reported a catalytic ef-
Even the very unreactive tertiary alcohol, 1-adamantanol fect of iodine in conjunction with the introduction of tri-
(entry 10), could be silylated in high yield, but the reaction methylsilyl group using 1,1,1,3,3,3-hexamethyldisilazane
had to be performed in neat N-methylimidazole in the (HMDS)14,15 or with silyl chlorides (TMSCl, TBDMSCl)
presence of six equivalents of iodine. On average, the re- under microwave irradiation;16 however, a mechanistic
actions in Table 1 were 5–30 times faster than those with- role of iodine in these and in our systems, seems to be dis-
out iodine under standard silylation conditions using silyl parate.
chloride and imidazole in DMF.5 The accelerating effect
In conclusion, we developed an efficient protocol for the
of the added iodine was largest for the slowest reactions
silylation of primary, secondary, and tertiary alcohols that
and in the extreme case (entry 10), the silylation could
consisted of using a silyl chloride in the presence of
only be carried under the new reaction conditions.
N-methylimidazole and iodine. The reactions can be car-
As it is apparent from Table 1, the reaction conditions for ried out in various organic solvent (e.g. THF, MeCN,
the silylation are compatible with the presence of double CH2Cl2, pyridine), at room temperature, and are compati-
and triple bonds, even when the corresponding reaction ble with the presence of common functional groups. The
mixtures were left standing for a longer time (5 h).
procedure is experimentally simple, high-yielding, and
expands the range of synthetic methods available for sily-
lation of complex organic compounds.
Synlett 2008, No. 1, 37–40 © Thieme Stuttgart · New York
Bartoszewicz, Agnieszka
