Palladium-Catalyzed Direct Arylation of 2-Pyridylmethyl Silanes with Aryl Bromides

Article abstract of DOI:10.1021/acs.orglett.1c00677

The first palladium-catalyzed direct arylation of 2-pyridylmethyl silanes with aryl bromides to generate a diverse array of aryl(2-pyridyl)-methyl silane derivatives has been developed. This protocol facilitates access to various kinds of heterocycle-containing silanes in good to excellent yields (40 examples, 66-97% yield) with good functional group tolerance. The scalability of this transformation is demonstrated.

Full text of DOI:10.1021/acs.orglett.1c00677

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Direct Arylation of 2‑Pyridylmethyl Silanes
with Aryl Bromides
Tingzhi Lin, Pengcheng Qian, Yan-En Wang, Mingjie Ou, Long Jiang, Chen Zhu, Yuchuan Xu,
Dan Xiong, and Jianyou Mao*
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ABSTRACT: The first palladium-catalyzed direct arylation of 2-
pyridylmethyl silanes with aryl bromides to generate a diverse array
of aryl(2-pyridyl)-methyl silane derivatives has been developed. This
protocol facilitates access to various kinds of heterocycle-containing
silanes in good to excellent yields (40 examples, 66−97% yield) with
good functional group tolerance. The scalability of this transformation is
demonstrated.
turned our attention to the deprotonative functionalization of
azaarylmethyl silanes.
rganosilanes are important structures that have found
Obroad applications ranging from silicon materials to
pharmaceuticals.1 They are also useful precursors in many
cross-coupling reactions2 and are used as ligands in transition-
metal coordination chemistry.3 Furthermore, the rapid
functionalization of heterocycles continues to attract much
attention in medicinal chemistry. Taken together, the demand
for a more general and straightforward synthesis of hetero-
cycle-containing silanes remains high,4 where the direct α-
functionalization of azaarylmethyl silanes represents one of the
ideal strategies.
The methods for α-functionalization of the existing
organosilanes include (1) the transition-metal-catalyzed
cross-coupling of silylated Grignard reagents with organo
halides5 (Scheme 1A) and (2) the nickel-catalyzed cross-
coupling process between α-silylated alkyl halides and vinyl
bromides6 or alkylzinc reagents7 (Scheme 1B). These methods
require prefunctionalization of the corresponding silanes.
Driven by the desire to simplify the starting materials, we
In recent years, a variety of functionalizations of weakly
3
acidic Csp −H bonds via deprotonative cross-coupling
processes were reported with substrates including diaryl-
methanes,8 sulfoxides,9 and amines,10 among others.11
However, the direct deprotonative cross-coupling of silanes
has not been explored. Herein we provide a methodology to
generate a variety of aryl(2-pyridyl)-methyl silane derivatives
via a deprotonative cross-coupling process with 2-pyridine
silane derivatives under mild conditions. This protocol avoids
using Grignard reagents, and the starting materials are easily
prepared and air-stable. Also, the products generated here
could be easily transferred to an aryl(2-pyridyl)methanol core
and are commonly found in drug candidates.12 Compared with
the existing methods for constructing organosilanes, such as
the hydrosilylation of terminal olefin,13 the transition-metal-
catalyzed cross-coupling of silicon electrophiles or nucleophi-
les,4a,14 and transition-metal-catalyzed C−H silylation,15 our
strategy provides an alternative synthesis of heterocycle
containing silanes (Scheme 1C).
We commenced our research by choosing Pd(OAc)2/
Nixantphos as the catalyst and 2-((trimethylsilyl)methyl)-
pyridine 1a and bromobenzene 2a as model starting materials
(Table 1). Initially, we screened different bases (LiN(SiMe3)2,
NaN(SiMe3)2, KN(SiMe3)2, LiOtBu, NaOtBu, and KOtBu) by
using THF (tetrahydrofuran) as the solvent at 40 °C for 12 h
(Table 1, entries 1−6). After the six bases were screened, we
Scheme 1. Transition-Metal-Catalyzed Functionalization of
Silanes
Received: February 25, 2021
Published: March 29, 2021
https://doi.org/10.1021/acs.orglett.1c00677
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3000−3003
3000

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a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Substrate Scope of Aryl Bromides
b
entry
base
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
LiN(SiMe3)2
NaN(SiMe3)2
KN(SiMe3)2
LiOtBu
THF
THF
THF
THF
THF
THF
THF
THF
toluene
dioxane
CPME
TBME
THF
40
40
40
40
40
40
40
40
40
40
40
40
60
80
76
68
71
57
53
52
trace
trace
0
39
60
63
96
89
NaOtBu
KOtBu
Et3N
DBU
9
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
LiN(SiMe3)2
10
11
12
13
14
THF
a
Reactions were conducted on a 0.1 mmol scale using 1a (1 equiv),
2a (2 equiv), Pd(OAc)2 (4 mol %), and Nixantphos (6 mol %), base
b
(3 equiv), and solvent (0.2 M). Yield determined by 1H NMR
spectroscopy of the crude reaction.
a
b
Reactions performed on a 0.2 mmol scale. 3.0 equiv of aryl bromide
was used.
observed that LiN(SiMe3)2 provided the best yield of the
desired cross-coupling product 3aa in 76% yield (Table 1,
entry 1). Other silylamide bases such as NaN(SiMe3)2 and
KN(SiMe3)2 proved less effective for this reaction, affording
the product in 68 and 71% yields, respectively (Table 1, entries
2 and 3). In contrast, MOtBu (M = Li, Na, K) exhibited low
efficiency (Table 1, entries 4−6). We also screened Et3N and
DBU as the base for this transformation; however, only a trace
cross-coupling product was found (Table 1, entries 7 and 8).
Next, LiN(SiMe3)2 was used going forward to study the effect
of solvents on the reactivity of this transformation (Table 1,
entries 9−12). This screen exhibited that non-chelation solvent
toluene did not afford the desired cross-coupling product at all
(Table 1, entry 9), and THF outperformed other ether
solvents (Table 1, entry 1 vs entries 10−12). To increase the
yield of 3aa, we next examined the impacts of temperature.
Increasing the temperature from 40 to 60 °C had a good effect
on the yield, affording the desired product in 96% isolated
yield (Table 1, entry 13); further increasing the temperature
from 60 to 80 °C decreased the yield to 89% (Table 1, entry
14). Ultimately, the best conditions for this transformation
were 2-((trimethylsilyl)methyl)pyridine (1a, 1.0 equiv),
bromobenzene (2a, 2.0 equiv), LiN(SiMe3)2 (3 equiv),
Pd(OAc)2 (4 mol %), Nixantphos (6 mol %), and THF (0.2
M) at 60 °C for 12 h.
With the optimized reaction conditions in hand, we next
explored the scope of aryl bromides with 2-((trimethylsilyl)-
methyl)pyridine 1a under the standard conditions (Scheme 2).
In general, it was proved that our conditions tolerated a variety
of functional groups, affording a wide range of aryl(2-pyridyl)-
methyl silane derivatives 3aa−3ar in good to excellent yields
(66−97%). The parent bromobenzene 2a reacted to give the
cross-coupling product 3aa in 96% isolated yield. Aryl
bromides containing electron-neutral and -donating groups,
such as 4-Me, 4-tBu, 4-Ph, 4-OMe, 4-SMe, and 4-NMe2
exhibited good to excellent reactivities, affording 3ab−3ag in
82−97% yields. In addition, substrates bearing electron-
withdrawing groups, such as 4-fluorobromobenzene 2h and
4-chlorobromobenzene 2i, proved to be suitable nucleophiles
as well, affording the corresponding products 3ah and 3ai with
excellent chemoselectivity. Then, sterically hindered aryl
bromides were applied in this transformation, such as 2-
bromotoluene 2j and 2,5-dimethylbromobenzene 2k as well as
2,5-dimethoxybromobenzene 2l, forming 3aj−3al in 76−93%
yields. We also found that meta-substituted reagents could be
utilized in this transformation, providing the desired products
3am−3ao in 71−93% yields. π-Extended substrates 2p and 2q
successfully underwent this transformation to afford 3ap and
3aq in 87−91% yields. In addition, heterocyclic N-methyl-5-
bromoindole 2r was compatible under our standard con-
ditions, generating the desired products 3ar in 66% yield.
Next, we turned our attention to different silanes (Scheme
3). In this part, we chose bromobenzene and 4-methylbromo-
benzene as electrophiles to couple to different silanes. In
general, these transformations proceeded well to produce the
corresponding products in moderate yields when triethylsilane
was used in this coupling process (3ba and 3bb, 88−90%
yields). Compared with triethylsilane 1b, triisopropylsilane 1c
exhibited slightly decreased reactivity, providing the desired
product 3cb in 79% isolated yield. Similarly, dimethyl(n-
propyl)silane 1d and dimethyl(n-butyl)silane 1e underwent
the desired deprotonative cross-coupling processes, providing
the corresponding products in good yields (3da, 3db, 3ea, and
3eb, 83−85% yields). Dimethyl(t-butyl)silane 1f was an
excellent substrate under our conditions, giving the corre-
sponding products 3fa and 3fb in >90% yield. It should be
noted that more sterically hindered silanes such as dimethyl-
(2,3-dimethylbutan-2-yl)silane 1g led to a slightly diminished
yield, providing the desired product 3gb in 77% yield. Next, we
extended one of the carbon chains of silanes (dimethyl(n-
octyl)silane 1h) to react with bromobenzene and 4-
3001
https://doi.org/10.1021/acs.orglett.1c00677
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a
Scheme 3. Substrate Scope of 2-Pyridylmethyl Silanes
Scheme 5. Transformations of the 2-Pyridylmethyl Silane
silanes with aryl bromides. Both electron-donating and
electron-withdrawing aryl bromides can undergo the cross-
coupling process with good to excellent reactivity. Further-
more, a diverse array of tetraorganosilanes are suitable for this
transformation. To the best of our knowledge, this method
represents the first palladium-catalyzed direct deprotonative
functionalization of silanes, although a reactive pyridine group
is needed in the current stage. Because of the significance of
these aryl(2-pyridyl)-methyl silane derivatives, we anticipate
that this methodology will find applications in medicinal
chemistry. Studies toward the functionalization of simple
silanes are ongoing in our laboratories
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00677.
a
Experimental details, characterization data, and NMR
spectra (PDF)
Reactions performed on a 0.2 mmol scale.
methylbromobenzene under standard conditions, giving 3ha
and 3hb in 89 and 85% yields, respectively. We were delighted
to observe that various aryl-substituted silanes were suitable
partners, generating the corresponding products 3ia, 3ib, 3ja,
3jb, 3ka, and 3kb in 72−84% yields. We continued to explore
the nature of the pyridine group. It was found that substituted
2-pyridines could provide the corresponding products in good
yields (3la−3oa, 74−94% yields). Unfortunately, alkyl group
(1p), simple phenyl group (1q), and other heterocycle groups
such as 1r and 3- and 4-pyridyl (1s and 1t) gave only trace
target products under the standard conditions. These findings
implied that 2-pyridyl-substituted silanes, which can coordinate
with the main group metal of the base, are needed in this
transformation.
AUTHOR INFORMATION
Corresponding Author
■
Jianyou Mao − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211800, P. R. China; orcid.org/0000-0003-0581-3978;
Email: ias_jymao@njtech.edu.cn
Authors
Tingzhi Lin − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211800, P. R. China
To test the scalability of this transformation, 5.0 mmol of 2-
((trimethylsilyl)methyl)pyridine 1a was coupled to bromo-
benzene 2a under the standard conditions (Scheme 4). The
desired cross-coupling product 3aa was isolated in 91% yield
(1.10 g).
Pengcheng Qian − Technical Institute of Fluorochemistry
(TIF), Institute of Advanced Synthesis, School of Chemistry
and Molecular Engineering, Nanjing Tech University,
Nanjing 211800, P. R. China
Yan-En Wang − College of Science, Hebei Agricultural
University, Baoding 071000, P. R. China
Mingjie Ou − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211800, P. R. China
Scheme 4. Scale-up the Transformation on 5.0 mmol Scale
Long Jiang − Institute of Advanced Synthesis (IAS),
Northwestern Polytechnical University (NPU), Xi’an
710072, China; Yangtze River Delta Research Institute of
NPU, Taicang, Jiangsu 215400, P. R. China
Chen Zhu − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211800, P. R. China
Yuchuan Xu − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211800, P. R. China
In addition, the aryl(2-pyridyl)methanol core is an
important building block that is widely utilized in drug
candidates;16 therefore, we tried to explore the transformation
of the C−Si bond to the C−O bond (Scheme 5). To our
delight, the C−O bond could be formed by using PIFA as the
oxidant, affording the desired product 4A in 62% yield.12
In summary, we have shown here that a broad array of
aryl(2-pyridyl)-methyl silane derivatives can be prepared by
the palladium-catalyzed cross-coupling of 2-pyridylmethyl
3002
https://doi.org/10.1021/acs.orglett.1c00677
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Letter
T.; Manor, B. C.; Tomson, N. C.; Walsh, P. J. J. Am. Chem. Soc. 2017,
139, 8337.
Dan Xiong − Technical Institute of Fluorochemistry (TIF),
Institute of Advanced Synthesis, School of Chemistry and
Molecular Engineering, Nanjing Tech University, Nanjing
211800, P. R. China
̈
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00677
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We acknowledge the National Natural Science Foundation of
China (21801128 and 22071107), Natural Science Foundation
of Jiangsu Province, China (BK20170965), Nanjing Tech
University (39837112), and Cultivation Program for Excellent
Doctoral Dissertation of Nanjing Tech University (2020-18)
for financial support.
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