Chemoselective Cleavage of Si-C(sp3) Bonds in Unactivated Tetraalkylsilanes Using Iodine Tris(trifluoroacetate)

Article abstract of DOI:10.1021/jacs.0c11645

Organosilanes are synthetically useful reagents and precursors in organic chemistry. However, the typical inertness of unactivated Si-C(sp3) bonds under conventional reaction conditions has hampered the application of simple tetraalkylsilanes in organic synthesis. Herein we report the chemoselective cleavage of Si-C(sp3) bonds of unactivated tetraalkylsilanes using iodine tris(trifluoroacetate). The reaction proceeds smoothly under mild conditions (-50 °C to room temperature) and tolerates various polar functional groups, thus enabling subsequent Tamao-Fleming oxidation to provide the corresponding alcohols. NMR experiments and density functional theory calculations on the reaction indicate that the transfer of alkyl groups from Si to the I(III) center and the formation of the Si-O bond proceed concertedly to afford an alkyl-λ3-iodane and silyl trifluoroacetate. The developed method enables the use of unactivated tetraalkylsilanes as highly stable synthetic precursors.

Full text of DOI:10.1021/jacs.0c11645

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Chemoselective Cleavage of Si−C(sp3) Bonds in Unactivated
Tetraalkylsilanes Using Iodine Tris(trifluoroacetate)
Keitaro Matsuoka, Narumi Komami, Masahiro Kojima, Tsuyoshi Mita, Kimichi Suzuki, Satoshi Maeda,
Tatsuhiko Yoshino,* and Shigeki Matsunaga*
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ABSTRACT: Organosilanes are synthetically useful reagents and precursors in organic chemistry. However, the typical inertness of
unactivated Si−C(sp3) bonds under conventional reaction conditions has hampered the application of simple tetraalkylsilanes in
organic synthesis. Herein we report the chemoselective cleavage of Si−C(sp3) bonds of unactivated tetraalkylsilanes using iodine
tris(trifluoroacetate). The reaction proceeds smoothly under mild conditions (−50 °C to room temperature) and tolerates various
polar functional groups, thus enabling subsequent Tamao−Fleming oxidation to provide the corresponding alcohols. NMR
experiments and density functional theory calculations on the reaction indicate that the transfer of alkyl groups from Si to the I(III)
center and the formation of the Si−O bond proceed concertedly to afford an alkyl-λ3-iodane and silyl trifluoroacetate. The developed
method enables the use of unactivated tetraalkylsilanes as highly stable synthetic precursors.
ilyl groups are stable and easy-to-handle synthetic
linchpins that can be converted into various functional
using a phenylthallium(III) complex (Scheme 1b).9 More
recently, Suginome and co-workers developed a stepwise
approach to convert trimethylsilyl groups into hydroxy groups
via Ir-catalyzed C−H borylation of a Me group and three
subsequent oxidative transformations in the presence of ester
or ether functionalities (Scheme 1c).10a However, only very
few oxygen-containing substrates were examined in those
reports. Thus, the development of general methods for the
cleavage of unactivated Si−C(sp3) bonds that can tolerate
various polar functional groups is important for the further
expansion of the application of tetraalkylsilanes in organic
chemistry.10b
S
groups via oxidation, halogenation, and cross-coupling
reactions.1 While transformations of arylsilane derivatives
have been widely studied, alkylsilanes have attracted less
attention in organic synthesis because of their lower reactivity.
A notable exception is the Tamao−Fleming oxidation,2 which
transforms alkylsilanes into the corresponding alcohols,
typically using peroxides and fluoride activators. These
protocols have often been employed in the total synthesis of
complex natural products.3 Nevertheless, to facilitate oxidation
of the silyl groups, the silicon atom must carry at least one
heteroatomic functional group or aryl/allyl substituent, which
can be selectively converted into a heteroatomic functional
group through electrophilic transformations.4 Simple, unac-
tivated tetraalkylsilanes are unreactive under conventional
organic synthesis reaction conditions, including those of the
Tamao−Fleming oxidation. The synthetic utility of trialkylsilyl
groups (e.g., −SiMe3 and −SiEt3) in aliphatic backbones has
scarcely been explored.5 However, the high stability of
tetraalkylsilanes and the low cost of some trialkylsilyl reagents
would make the application of tetraalkylsilanes as synthetic
precursors attractive if the Si−C(sp3) bond could be cleaved
under mild reaction conditions.
Herein we report the chemoselective cleavage of Si−C(sp3)
bonds in unactivated tetraalkylsilanes containing a wide range
of polar functional groups using iodine tris(trifluoroacetate)
(ITT) (Scheme 1d). We discovered that ITT reacts with
various tetraalkylsilanes under mild reaction conditions (−50
°C to room temperature) to cleave Si−C(sp3) bonds. The
resulting intermediates can be further converted into the
corresponding alcohols via subsequent oxidation with H2O2.
During our studies on the reactivity of ITT and I(OAc)3 in
organic synthesis,11,12 we envisioned that the high electro-
philicity of ITT could potentially enable the cleavage of
unreactive electron-rich covalent bonds, including Si−C(sp3)
bonds. We initially attempted the reaction of ITT with Me4Si
(A) in CDCl3 at room temperature (Scheme 2). To our
delight, the cleavage of one Si−C(sp3) bond of A proceeded
Cleavage of the Si−C(sp3) bonds in unactivated tetraalkyl-
silanes has to date mainly been accomplished by proto-
desilylation reactions using strong Brønsted acids,6 redistrib-
ution reactions using strong Lewis acids,7 or oxidation
reactions using highly electrophilic reagents.8 In most of
those previous studies, the substrates have been limited to
Me4Si or other tetraalkylsilanes that do not carry polar
functional groups, and the functional group tolerance has not
yet been investigated (Scheme 1a). In 1993, Murai and co-
workers reported the oxidative cleavage of unactivated Si−
C(sp3) bonds in a hydroxy-group-containing tetraalkylsilane
Received: November 6, 2020
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© XXXX American Chemical Society
A

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Scheme 1. Cleavage of Si−C(sp3) Bonds of Unactivated
Tetraalkylsilanes
were identified (Figure 1). The reaction pathway involves the
slightly unstable conformational isomer ITT_II. The electro-
Figure 1. Gibbs free energy diagram for the reaction of Me4Si (A)
with ITT, calculated at the M06-2X/def2-TZVPPD+SMD-
(CH2Cl2)//M06-2X/def2-SVP level of theory.
philic transfer of Me from A to the I(III) center of ITT_II and
the formation of the Si−O bond proceed in a concerted
fashion. In this transition state, the I(III) center attacks the Me
group from the side opposite the silicon atom. Similar
electrophilic methyl inversion has been reported by Qu and
Oestreich in their protodesilylation reaction.6f,g The calculated
activation energy is qualitatively reasonable (22.1 kcal mol−1),
and the formation of B and C is highly exergonic (−61.4 kcal
mol−1).
Subsequently, we examined the reaction of tetraalkylsilanes
with ITT followed by Tamao−Fleming oxidation using H2O2
to establish a method for the conversion of a trialkylsilyl group
to a hydroxy group in larger organic molecules (Table 1).
Treatment of decyltrimethylsilane (1a) with ITT in CH2Cl2 at
room temperature and subsequent workup with an aqueous
solution of Na2S2O3/NaHCO3 provided the decyldimethylsilyl
Scheme 2. Reaction of Me4Si (A) with ITT as Determined
Using NMR Analysis
Table 1. Investigation of the Cleavage of the Si−C(sp3)
a
Bond in Decyltrimethylsilane (1a) with ITT
smoothly to afford trimethylsilyl trifluoroacetate (Me3SiOTFA,
B) and methyl trifluoroacetate (MeOTFA, D), as confirmed
1
via H and 19F NMR analysis (for details, see Figures S1 and
S2). On the basis of this result and the fact that the I(III)
center of ITT is highly electrophilic,11,12 we speculated that the
reaction would initially afford methyl-λ3-iodane C via electro-
philic Me transfer to form the I(III)−Me bond. Subsequently,
C could be decomposed into D.13
To support this hypothesis, we carried out density functional
theory (DFT) calculations of the reaction of A with ITT at the
M06-2X/def2-TZVPPD+SMD(CH2Cl2)//M06-2X/def2-SVP
level of theory. While a dimeric crystal structure has been
reported for ITT,12d our DFT calculations suggested that the
monomeric structure ITT_I is more stable in solution. After
intensive investigations, the transition-state structure and
reaction pathway leading to electrophilic Si−Me cleavage
b
entry
temp. (°C)
yield (%)
1
2
3
4
r.t.
>95
>95
>95
57
−20
−40
−60
a
Reaction conditions: (1) 1a (0.05 mmol) and ITT (0.53 equiv) in
CH2Cl2 (0.5 mL) for 16 h at the indicated temperature; (2) for details
of the Tamao−Fleming oxidation, see the Supporting Information.
b
The yields of alcohol 4a were determined by 1H NMR analysis of the
crude reaction mixtures using 1,1,2,2-tetrachloroethane as an internal
standard.
B
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d
Scheme 3. Substrate Scope of Alcohol Synthesis through Cleavage of a Si−C(sp3) Bond in Tetraalkylsilanes 1−3
a
b
c
d
ITT (0.50 equiv). ITT (0.75 equiv). With BF3•OEt2 (1.1 equiv) as an additive. Reaction conditions: (1) 1, 2, or 3 (0.3 mmol) and ITT (0.53
equiv) in CH2Cl2 (3 mL), unless otherwise noted. The reaction temperature and time are shown in parentheses; (2) for details of the Tamao−
Fleming oxidation, see the Supporting Information.
intermediate almost quantitatively via selective cleavage of the
smallest alkyl group, i.e., the methyl group (for details, see
Figure S3). This selectivity should probably be attributed to
steric hindrance. This intermediate was then converted into
the corresponding alcohol 4a in high yield under Tamao−
Fleming oxidation conditions using H2O2 and fluorides14
(entry 1). ITT also reacted with 1a at lower temperatures
(entries 2−4), and the reaction proceeded in moderate yield
even at −60 °C (entry 4). As control experiments, we
examined the reactions of 1a with several λ3-iodanes and
I(OAc)3 instead of ITT. In these cases, no reaction proceeded
even at room temperature (for details, see Scheme S1).
We applied the established method to various tetraalkylsi-
lanes bearing functional groups (Scheme 3). In all cases, the
product was isolated and characterized as the corresponding
alcohol. In addition to the trimethylsilyl group (1a), a
triethylsilyl group (2a) and tert-butyldimethylsilyl group (3a)
were also converted into a hydroxy group in good to moderate
yields. Although the cleavage of the Si−C(sp3) bonds by ITT
proceeded in high conversion, the steric hindrance of the silyl
group may have reduced the reactivity of the subsequent
Tamao−Fleming oxidation,5d leading to the observed lower
yields of 4a from 2a and 3a compared with 1a. Secondary
alkylsilanes also provided the corresponding secondary
alcohols (4b, 4c). Tetraalkylsilanes bearing a broad range of
carbonyl groups, a cyano group, protected amines, and
alcohols could also be used in this reaction by adjusting the
reaction temperature (1d, 1e, 2f−o). Notably, an active
methylene moiety, which often reacts with hypervalent iodine
compounds,15 was also tolerated (2i). In some cases (2h, 2j,
2l, 2p, 2x), electrophilic ethylation of the polar functional
groups was observed, probably via an in situ-generated ethyl-
λ3-iodane as a strong electrophile. In situ protection of the
Lewis basic functional groups of these substrates with BF3·
OEt2 was effective in circumventing the competing alkylation
and promoting chemoselective Si−C(sp3) bond cleavage.16 We
successfully obtained the desired alcohols in the presence of
acid-sensitive Boc and TIPS moieties (4l, 4m) and an
oxidizable free hydroxy group (4p), demonstrating the polar
functional group tolerance of our method. Alkylsilanes
containing a synthetically useful Weinreb amide or phospho-
nate moiety also afforded the corresponding alcohols (4h, 4q)
C
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a
Scheme 4. Application in the Multistep Synthesis of Functionalized Molecules
a
For detailed reaction conditions, see the Supporting Information.
in 56 and 87% yield, respectively. Some halogen substituents
and nitrogen-containing heteroarenes were compatible with
our method (2r, 2s, 1t−w). In addition, as multifunctionalized
substrates, alkylsilanes derived from nalidixic acid and
probenecid afforded the corresponding alcohols 4x and 4y in
good yields. Moreover, we performed a large-scale reaction
using 5.3 mmol of 1a to afford the corresponding alcohol 4a in
85% yield, demonstrating the scalability of our developed
protocol. On the other hand, substrates with a terminal alkene
or an electron-rich aryl moiety were unsuccessful because of
competing reactions of such functional groups with ITT
(Figure S4).17
To demonstrate the synthetic advantages arising from the
high stability of tetraalkylsilanes, we investigated the
application of the developed method in the multistep synthesis
of functionalized molecules under various reaction conditions
that could potentially affect less stable synthetic precursors for
alcohols, such as organoborons (Scheme 4).18 Initially, we
examined the electrophilic aromatic nitration of tetraalkylsilane
1d with fuming nitric acid and concentrated sulfuric acid in
Ac2O.19 The reaction proceeded efficiently without proto-
desilylation or oxidation of the trimethylsilyl group to afford 5
in 93% yield. The synthesized tetraalkylsilane 5 was then
converted into the corresponding alcohol 6 via ITT oxidation/
Tamao−Fleming oxidation in 78% yield. Next, we oxidized
primary alcohol 7 to carboxylic acid 8 in good yield using
NaClO2/NaClO/TEMPO.20 Carboxylic acid 8 was further
derivatized via acyl chloride formation and subsequent AlCl3-
mediated intramolecular Friedel−Crafts acylation to afford
indanone 9. In these transformations, the trimethylsilyl group
remained intact. The tetraalkylsilane derived from indanone 9
was also converted into the corresponding alcohol 10.
Furthermore, we conducted an Ir-catalyzed C−H borylation21
of the aryl ring in tetraalkylsilane 11 and subsequent Suzuki−
Miyaura cross-coupling with aryl bromide 13 to obtain biaryl
derivative 14 in good yield without loss of the trimethylsilyl
group. Multifunctionalized biaryl 14 was also a suitable
substrate for the developed method, affording alcohol 15 in
60% yield.
In summary, we have developed a method for the
chemoselective cleavage of Si−C(sp3) bonds in unactivated
tetraalkylsilanes that contain several polar functional groups
using iodine tris(trifluoroacetate). The application of this
method to the multistep synthesis of functionalized molecules
without loss of the trimethylsilyl groups demonstrated the
synthetic utility of unactivated tetraalkylsilanes as inexpensive
and highly stable masked alcohols. Our findings can be
expected to induce further studies of the synthesis and
utilization of tetraalkylsilanes in organic chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11645.
Experimental procedures and spectral data for all new
compounds (PDF)
Cartesian coordinates (XYZ)
D
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Peroxide Oxidation of the Silicon-Carbon Bond in Organoalkox-
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Henning, R.; Plaut, H. The Phenyldimethylsilyl Group as a Masked
Form of the Hydroxy Group. J. Chem. Soc., Chem. Commun. 1984,
29−31.
AUTHOR INFORMATION
■
Corresponding Authors
Shigeki Matsunaga − Faculty of Pharmaceutical Sciences and
Global Station for Biosurfaces and Drug Discovery, Hokkaido
University, Sapporo 060-0812, Japan; orcid.org/0000-
0003-4136-3548; Email: smatsuna@pharm.hokudai.ac.jp
Tatsuhiko Yoshino − Faculty of Pharmaceutical Sciences,
Hokkaido University, Sapporo 060-0812, Japan;
orcid.org/0000-0001-9441-9272; Email: tyoshino@
pharm.hokudai.ac.jp
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Synthetic Approach to the Illicium Sesquiterpenes. J. Am. Chem. Soc.
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A. The Total Synthesis of Chalcitrin. J. Am. Chem. Soc. 2019, 141,
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Bisnucleophiles: A Concise Enantioselective Total Synthesis of
(−)-Englerin A and B. Angew. Chem., Int. Ed. 2019, 58, 8346−
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Authors
Keitaro Matsuoka − Faculty of Pharmaceutical Sciences,
Hokkaido University, Sapporo 060-0812, Japan
Narumi Komami − Faculty of Pharmaceutical Sciences,
Hokkaido University, Sapporo 060-0812, Japan
Masahiro Kojima − Faculty of Pharmaceutical Sciences,
Hokkaido University, Sapporo 060-0812, Japan;
orcid.org/0000-0002-4619-2621
Tsuyoshi Mita − Institute for Chemical Reaction Design and
Discovery (WPI-ICReDD), Hokkaido University, Sapporo
001-0021, Japan; JST, ERATO Maeda Artificial Intelligence
for Chemical Reaction Design and Discovery Project,
Sapporo, Hokkaido 060-0810, Japan; orcid.org/0000-
0002-6655-3439
Kimichi Suzuki − Institute for Chemical Reaction Design and
Discovery (WPI-ICReDD) and Department of Chemistry,
Faculty of Science, Hokkaido University, Sapporo 001-0021,
Japan; JST, ERATO Maeda Artificial Intelligence for
Chemical Reaction Design and Discovery Project, Sapporo,
Hokkaido 060-0810, Japan; orcid.org/0000-0002-4080-
5036
Satoshi Maeda − Institute for Chemical Reaction Design and
Discovery (WPI-ICReDD) and Department of Chemistry,
Faculty of Science, Hokkaido University, Sapporo 001-0021,
Japan; JST, ERATO Maeda Artificial Intelligence for
Chemical Reaction Design and Discovery Project, Sapporo,
Hokkaido 060-0810, Japan; orcid.org/0000-0001-8822-
1147
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11645
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS KAKENHI Grant
JP19K22177 (S. Matsunaga) and JST-ERATO Grant
JPMJER1903 (S. Maeda).
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