C-O Bond Silylation Catalyzed by Iron: A General Method for the Construction of Csp2-Si Bonds

Article abstract of DOI:10.1021/acs.orglett.0c00633

The iron-catalyzed construction of Csp²-Si bonds via unreactive C-O bonds possesses a challenging topic in organic chemistry. Herein we report an iron-catalyzed silylation of aryl and alkenyl carbamates via C-O bond activation. This protocol fe

Full text of DOI:10.1021/acs.orglett.0c00633

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Letter
C−O Bond Silylation Catalyzed by Iron: A General Method for the
Construction of Csp2−Si Bonds
Juan Zhang, Yun Zhang, Shasha Geng, Shuo Chen, Zhengli Liu, Xiaoqin Zeng, Yun He,
and Zhang Feng*
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ABSTRACT: The iron-catalyzed construction of Csp2−Si bonds
via unreactive C−O bonds possesses a challenging topic in organic
chemistry. Herein we report an iron-catalyzed silylation of aryl and
alkenyl carbamates via C−O bond activation. This protocol
features high efficiency and a broad substrate scope, enabling the
late-stage silylation of biorelevant compounds and thus providing a
good method to access valuable motifs in medicinal chemistry.
Moreover, this protocol enables orthogonal transformations of
phenol derivatives and also allows for the synthesis of multi-
substituted arenes through the carbamate group as the directing
group.
ron catalysts have been widely used in cross-coupling
reactions owing to their cheapness, abundance, and
Scheme 1. Transition-Metal-Catalyzed Construction of C−
Si Bonds
I
nontoxicity.1 To facilitate the oxidative addition in iron-
catalyzed cross-coupling reactions, a highly reactive, low-valent
iron species always needs to be generated through sacrificial
organometallic reagents via reductive elimination in situ.2
Consequently, these reactions are mostly limited to the
formation of C−C bonds through classical cross-coupling
reactions,3 and the iron-catalyzed construction of C−
heteroatom bonds has lagged.4 Organosilicon compounds are
important reagents that are widely employed in organic
synthesis, material science, as well as medicinal chemistry.5
However, iron-catalyzed cross-coupling reactions to construct
C−Si bonds have been less developed.6,7 It is of great interest
to develop an organometallic reagent-free and efficient iron-
catalyzed method for the construction of C−Si bonds.
Compared with organohalides, oxygen-based electrophiles,
such as phenol and ketone derivatives, have become
increasingly more attractive as the coupling partners.8 Not
only are phenols and ketones commercially available and easily
produced but also the halide-containing waste is avoided by
using oxygen-based electrophiles. The silylation of unreactive
C−O bonds has been carried out by the Martin group,9 but the
formation of alkenylsilanes has been less explored.9b The
transmetalation process of silicon nucleophiles is more sluggish
than that of other organometallic reagents. To address this
issue, metal-based silicon nucleophiles are always used in cross-
coupling reactions. For example, pioneering works were
reported by the Oshima and Trost groups,10 in which the
aluminum-based silicon reagents were used (Scheme 1). Very
recently, Oestreich and coworkers reported the copper-
Received: February 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00633
© XXXX American Chemical Society
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a
Table 1. Representative Results for the Optimization of the Iron-Catalyzed Silylation of Naphthalen-1-yl Diethylcarbamate 1a
b
entry
[Fe]
ligand
solvent
toluene
toluene
toluene
toluene
base
yield (%)
1
2
3
4
5
6
7
8
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
Fe(OTf)2
FeBr2
P(t-Bu)3
P(p-MePh)3
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
MeOK
MeOK
MeOK
0
28
36
23
60
28
64
78
t-BuONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
MeONa
toluene
(i-Pr)2O
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
10
11
Fe(OAc)2
Fe(OAc)2
93 (89)
0
0
XPhos
a
Reaction conditions (unless otherwise specified): 1a (0.3 mmol, 1.0 equiv), silylborane 2a (0.75 mmol, 2.5 equiv), [Fe] (0.015 mmol, 0.05 equiv),
b
1
ligand (0.03 mmol, 0.1 equiv), solvent (1.5 mL), base (1.05 mmol, 3.5 equiv), 120 °C, 15 h. Determined by H NMR using mesitylene as an
internal standard. The isolated yield is shown in parentheses.
catalyzed silylation of vinyliodonium triflate with silylzinc
reagents (Scheme 1).11 Although those achievements have
been made, it should be noted that the synthesis of tetra-
substituted alkenylsilanes remains challenging. Moreover, the
iron-catalyzed formation of C−Si bonds with unreactive C−O
bonds has yet to be achieved, owing to the problematic
oxidative addition step with iron catalysts due to their strong
bond dissociation energy.12 To continue our interest in
transition-metal catalysis,13 herein we describe an example of
the construction of Csp2−Si bonds from phenol and ketone
derivatives through iron-catalyzed C−O bond activation
without Grignard reagents,14 thus providing a facile and
efficient route to the synthesis of tri- and tetra-substituted
alkenylsilanes.
With these considerations in mind, we began to search for
the potential oxygen-based electrophiles for the iron-catalyzed
silylation. Among the oxygen-based electrophiles, aryl
carbamates are rather attractive due to their ease of preparation
and high stability.15 Moreover, the carbamate group has been
widely employed as the directing group to realize regioselective
C−H bond functionalization or electrophilic aromatic
substitution, providing the chance for orthogonal trans-
formations.16 Accordingly, we began our investigations by
subjecting aryl carbamate 1a to silylborane 2a in the presence
of various bases and electron-rich ligands, such as P(t-Bu)3 and
P(Cy)3, but no desired product was observed. (For details, see
the Supporting Information.) To our delight, after extensive
investigations, the silylated product 3 was observed in 28%
yield when P(p-MePh)3 was used as a ligand (Table 1, entry
2). Encouraged by these results, other parameters were
evaluated (Table 1, entries 3−5), and the desired product 3
was obtained in a promising 60% yield when sodium
methanolate was used as a base in the presence of XPhos as
the ligand (Table 1, entry 5). Switching the solvent from
toluene to ethers provided the corresponding compound in
moderate yield (Table 1, entries 5−7). After testing other iron
sources, we found that FeBr2 could promote this reaction,
providing 3 in 78% yield. Furthermore, Fe(OAc)2 could
drastically improve the reaction efficiency, delivering 3 in 89%
isolated yield (Table 1, entries 8 and 9; for details, see the
Supporting Information). Control experiments revealed the
necessity for both an iron catalyst and a ligand, and no desired
product was observed in the absence of an iron catalyst or
XPhos. These results suggest that electron-rich ligand XPhos
plays a crucial role in promoting this reaction. This is probably
because the electron-rich ligand could facilitate the oxidative
addition of an unreactive C−O bond to the iron catalyst.
After the optimal conditions were established, the scope of
this iron-catalyzed silylation reaction was explored. As shown
in Scheme 2, when naphthyl phenol derivatives were used as
substrates, this reaction proceeded well, providing the
corresponding silylated products in good to excellent yield
(3−10, 68−94%). Substrates bearing a strong electron-
donating group afforded the desired products in good yield
(5−7, 68−74%). In addition, the naphthyl carbamates
containing an aryl group on the aromatic ring proceeded
smoothly, and the corresponding products were obtained in
good yield (8−10, 72−89%). Polycyclic aromatic substrates
also showed good reactivity, affording the silylated products in
moderate to good yield (11−14, 66−81%), and the N-
heteroaromatic carbamate could undergo this transformation
as well, producing 15 in a synthetically useful yield. Biphenyl
substrates were demonstrated to be good reaction partners,
resulting in the corresponding products in moderate yield (16
and 17, 57−64%). To our delight, relatively inert monophenyl
substrates also proceeded smoothly, yielding the corresponding
products in moderate to good yield (18−31, 50−81%).
Moreover, the silyl and alkynyl groups were well-tolerated, and
18 was afforded in an excellent yield (81%), providing an
opportunity for the further modification of aryl silanes.
Importantly, this silylation reaction could be extended to
alkenyl carbamates, and the corresponding silylated products
were obtained in moderate to good yield. For a carbamate
group located at the one- or two-position of cyclic styrene
derivatives, the transformation proceeded smoothly (32−48).
Functional groups such as CF3, Cl, F, OBn, carbamate, and 2-
pyridyloxy could be well-tolerated (45, 46, 47, 50, 51, and 52).
It is worth noting that the relatively unreactive alkenyl
carbamates without the π-extended conjugated system could
react well (49−53). Linear carbamate bearing a bulky group
B
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a
Scheme 2. Scope of the Iron-Catalyzed Silylation of Aryl and Alkenyl Carbamates
a
Reaction conditions: aryl carbamates (0.3 mmol, 1.0 equiv), silylborane 2a (0.75 mmol, 2.5 equiv), Fe(OAc)2 (0.015 mmol, 0.05 equiv), XPhos
b
(0.03 mmol, 0.1 equiv), 1,4-dioxane (1.5 mL), MeONa (1.05 mmol, 3.5 equiv), 120 °C, 15 h. Aryl carbamates (0.2 mmol, 1.0 equiv), silylborane
2a (0.64 mmol, 3.2 equiv), [Fe] (0.02 mmol, 0.1 equiv), dtbpy (0.02 mmol, 0.1 equiv), MTBE (1.5 mL), MeONa (0.8 mmol, 4.0 equiv) was used.
(For details, see the Supporting Information.) Alkenyl carbamates (0.2 mmol, 1.0 equiv), silylborane 2a (0.5 mmol, 2.5 equiv), Fe(OAc)2 (0.02
c
mmol, 0.1 equiv), Xantphos (0.024 mmol, 0.12 equiv), MTBE (2.0 mL), MeONa (0.8 mmol, 4.0 equiv), 100 °C, 15 h. The isolated yield on a 1
d
mmol scale is shown in parentheses. Alkenyl carbamates (0.2 mmol, 1.0 equiv), silylborane 2a (0.6 mmol, 3.0 equiv), Fel2 (0.02 mmol, 0.1 equiv),
BINAP (0.024 mmol, 0.12 equiv), MTBE (1.0 mL), MeONa (0.8 mmol, 4.0 equiv), 100 °C, 15 h. (For details, see the Supporting Information.)
was also suitable for this reaction, providing the silylated
product in moderate yield (53, 48%). Moreover, this
transformation could be used to synthesize tetra-substituted
alkenylsilane, providing the desired product in an acceptable
yield (54, 35%).
To further demonstrate the inherent value of this protocol,
the late-stage silylation of biorelevant compounds, such as
estrone and vitamin E carbamates, was conducted (Scheme 3).
The desired products were delivered in moderate yield (55 and
56, 48−58%), providing facile access to diversified bioactive
molecules from phenol structures. Most remarkably, the
versatile utilities of this protocol can be demonstrated by
meta-arylation through C−H bond activation using carbamate
as the directing group, followed by silylation via iron catalysis.
The introduction of a meta-aryl group on naphthyl carbamates
via C−H bond activation followed by silylation via iron
catalysis allows for the synthesis of the silylated compounds in
moderate yield (57 and 58, 44−72%).17 These results suggest
that these iron-catalyzed silylation protocols could not only
enable the diversification of phenol derivatives but also provide
an efficient method to synthesize valuable molecules, meta-
substituted arenes in medicinal chemistry.
To gain insight into the mechanism of this iron-catalyzed
C−O bond activation reaction, radical inhibition experiments
were conducted. Drastically diminished yields were observed
when one equivalent of a radical scavenger TEMPO or a
radical inhibitor BHT was added under the standard silyation
reaction conditions (Scheme 4A), indicating that a radical
pathway might be involved. In these reactions, the adduct of
TEMPO with an aryl radical was not observed by LC−MS.
Furthermore, the electron paramagnetic resonance experi-
ments were also conducted, which suggested that a free radical
C
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C−H bond functionalization of aromatic rings, providing good
opportunities for the diversification of silylated derivatives.
Further studies to illustrate the mechanism and expand this
novel transformation are under way in our lab, and the results
will be reported in due course.
Scheme 3. Late-Stage Functionalization of Biomolecules
and Orthogonal Transformations of Phenols
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00633.
Experimental data and copies of 1H NMR and 13C NMR
spectra for all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Zhang Feng − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, Chemical Biology Research
Center, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China; Sichuan Key
Laboratory of Medical Imaging & Department of Chemistry,
School of Preclinical Medicine, North Sichuan Medical College,
Nanchong, Sichuan 637000, China; orcid.org/0000-0001-
7776-8200; Email: fengzh@cqu.edu.cn
Scheme 4. Mechanistic Studies
Authors
Juan Zhang − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, Chemical Biology Research
Center, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China
Yun Zhang − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, Chemical Biology Research
Center, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China
Shasha Geng − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, Chemical Biology Research
Center, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China
Shuo Chen − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, Chemical Biology Research
Center, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China
Zhengli Liu − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, Chemical Biology Research
Center, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China
Xiaoqin Zeng − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, Chemical Biology Research
Center, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China
Yun He − Chongqing Key Laboratory of Natural Product
Synthesis and Drug Research, Chemical Biology Research
Center, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, P. R. China; orcid.org/
0000-0002-5322-7300
was involved in this catalytic system (Scheme 4B; for details,
see the Supporting Information). Moreover, a radical clock
experiment was carried out as well (Scheme 4C). The radical
ring-opening product 60 was not observed, suggesting that a
silane radical species may not be involved in this catalytic
system.
In conclusion, we have developed the first example of the
iron-catalyzed silylation of aryl and alkenyl carbamates via C−
O bond activation. This reaction features simple operation,
high efficiency, and a broad substrate scope. It could be applied
for the late-stage silylation of bioactive compounds, offering
potential applications in drug discovery and development.
Furthermore, the carbamate directing group could facilitate the
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00633
Notes
The authors declare no competing financial interest.
D
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ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (no. 21801029),
Graduate Scientific Research and Innovation Foundation of
Chongqing (no. CYS18046), 100 Talent Plan from Chongqing
University (0247001104405), Sichuan Key Laboratory of
Medical Imaging (North Sichuan Medical College, no.
SKLMI201901), and Natural Science Foundation of Chongq-
ing (nos. cstc2019jcyj-msxmX0048). We thank Prof. Xingang
Zhang (Shanghai Institute of Organic Chemistry) and Prof.
Gang Li (Utah State University) for helpful discussions.
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of Silicon-Containing Compounds. Angew. Chem., Int. Ed. Engl. 1989,
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