Base-Mediated Borylsilylation/Silylation of Ammonium Salts with Silylborane

Article abstract of DOI:10.1021/acs.orglett.1c02066

This work describes a base-mediated borylsilylation of benzylic ammonium salts to synthesize geminal silylboronates bearing benzylic proton under mild reaction conditions. Deaminative silylation of aryl ammonium salts was also achieved in the presence of

Full text of DOI:10.1021/acs.orglett.1c02066

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Letter
Base-Mediated Borylsilylation/Silylation of Ammonium Salts with
Silylborane
Wan-Ying Qi, Jing-Song Zhen, Xiao-hong Xu, Xian Du, Yi-hui Li, Han Yuan, Yun-Shi Guan, Xun Wei,
Zi-Ying Wang, Guohai Liang,* and Yong Luo*
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ABSTRACT: This work describes a base-mediated borylsilylation of
benzylic ammonium salts to synthesize geminal silylboronates bearing
benzylic proton under mild reaction conditions. Deaminative silylation
of aryl ammonium salts was also achieved in the presence of LiOtBu.
This strategy which is featured with high efficiency, mild reaction
conditions, and good functional group tolerance provides efficient
routes for late-stage functionalization of amines.
onstruction of C−Si bonds1 draws extensive and
Scheme 1. Borylsilylation/Silylation of Ammonium Salts
with Silylborane
C
continuous efforts in the last few decades since silyl
groups can not only serve as cross-coupling partners in organic
synthesis2 but also play important roles in pharmaceuticals3
and material science.4 Among the various silanes, 1,1-
silylboronate esters is particularly appealing because this
nonsymmetric dimetallic unit would largely increase the
diversity and complexity of the products through further
transformations. In recent years, transition-metal-catalyzed
cross-coupling,5 hydroborylation,6 and hydrosilylation7 toward
geminal silylboronates have been well-developed. Transition-
metal-free borylsilylation has also been achieved with using
diazo compounds.8 As an alternative pathway, Aggarwal9 and
several groups10 developed efficient routes for borylsilylation of
lithiated carbamates to synthesize 1,1-silylboronate esters in
which a carbamate group derived from alcohol served as a
leaving group along with the 1,2-shift of the silyl unit (Scheme
1a). They also found that benzylic proton could not survive in
this reaction, probably due to its instability under the strong
basic conditions.
Considering the wide existence of amine groups in
chemicals, converting amines to nonsymmetric dimetallic
reagents would largely increase their potential utilities. And
owing to the inertness of C−N bonds, transforming amine
groups to ammonium salts11 is one of the most efficient
strategies to promote C−N bond functionalization.12 We
believed that as a stronger activator, ammonium salts in the
benzylic position, would require a weaker base for deproto-
nation, which would make the benzylic proton in the product
remain intact. However, benzylic ammonium salts were found
to proceed deaminative silylation with copper catalyst (Scheme
1b).13 Different from this pathway, we disclose here a base-
mediated borylsilylation of benzylic ammonium salts to
provide 1,1-silylboronate esters bearing benzylic proton.
Moreover, deaminative silylation of aromatic ammonium
salts could also be achieved under basic conditions (Scheme
1c). These strategies are featured with high efficiency, mild
reaction conditions, and good functional group tolerance,
providing efficient pathways for late-stage functionalization of
amines.
The initial exploration was commenced with benzylic
ammonium triflate 1a, silylborane 2a, and base in the absence
of transition metals (Table 1). LDA was found to provide 8%
Received: June 20, 2021
Published: July 9, 2021
https://doi.org/10.1021/acs.orglett.1c02066
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5988−5992
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a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Benzylic Ammonium Salts
entry
base
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
LDA
toluene
toluene
toluene
toluene
toluene
THF
DME
toluene
toluene
0
0
0
0
0
0
0
rt
−20
8
nd
22
81
82
7
trace
62
LiOtBu
LiHMDS
NaHMDS
KHMDS
KHMDS
KHMDS
KHMDS
KHMDS
77
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), base (0.22
mmol, 1.0 M in THF), solvent (1.0 mL), 3 h. DME = 1,2-
dimethoxyethane.
yield of the desired product 3a in toluene at 0 °C (entry 1).
Weaker base LiOtBu could not afford any product (entry 2).
Better results were obtained using LiHMDS, and 22% yield of
3a was isolated (entry 3). NaHMDS improved the yield to
81% (entry 4). KHMDS was the best base, affording 82%
isolated yield of 3a (entry 5). It worth noting that premixing
the base and substrate required in other protocols9,10 was not
needed in this procedure. Silylborane 2a and the base were
added to the solution of ammonium salt 1a in toluene at
nitrogen atmosphere sequentially, which renders a convenient
and easy-to-handle pathway for synthesis of gem- silylboro-
nates. Other solvents such as THF and DME showed
inefficiency with KHMDS (entries 6 and 7). A higher (room
temperature) or lower reaction temperature (−20 °C) led to
lower yields (entries 8 and 9).
The scope of benzylic ammonium salts was tested in the
next step (Scheme 2). Substrate with a tert-butyl group on the
para-position resulted in 3b with 92% yield. A methyl group on
the meta- or ortho-position afforded moderate yields, 76% and
69%, respectively (3c and 3d). Substrates with strong electron-
donating groups could also be utilized in this reaction. 4-
Methoxyl and 4-trifluoromethoxyl groups were tolerated under
the reaction conditions (3e and 3f), while −20 °C was
required for the 3,5-dimethoxyl group attached benzylic
ammonium salt to achieve a satisfisfactory yield of 3g.
Biphenyl and naphthyl group-containing 1,1-silylboronate
esters 3h−3j were synthesized with mild to good efficiency
by this strategy. Moreover, product 3i could be synthesized
with 75% yield in 1 mmol scale. Fluorine and chlorine atoms
remained intact under the reaction conditions (3k−3m).
Strong electron-withdrawing groups such as ester, trifluor-
omethyl, and nitrile groups needed a lower temperature or
weaker base (3n−3q), probably because of the higher
reactivity of the benzylic proton. Remarkably, the allyl
ammonium salts could also provide the corresponding product
3r with 53% yield at −20 °C. This method met some
difficulties in synthesizing bulky or heterocyclic silylboranes.
Only a trace of 3s was detected because of the steric hindrance,
and the furan ring probably was incompatible with the strong
base, providing only a trace of 3t. Attempts to synthesize
aliphatic silylborane 3u have failed due to the inertness of the
C−H bond in tetramethylammonium salt.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), KHMDS (0.22
b
mmol, 1.0 M in THF), solvent (1.0 mL), 0 °C, 3 h. −20 °C.
c
LiHMDS (0.22 mol, 1.0 M in THF).
toward aryl silanes.14 Zhang and co-workers reported
transition-metal-free silylation of electron-deficient aryl ammo-
nium salts with hexamethyldisilane.15 We wondered about the
efficiency of our reaction system in the silylation of aryl
ammonium salts. Therefore, base-mediated silylation of
substrate 4a with silylborane 2a was tested in the presence
of various reaction conditions (Table S1). The best result
(83% yield) was obtained in the presence of LiOtBu in THF at
55 °C. The scope of aryl ammonium triflates was investigated
subsequently (Scheme 3). A p-aryl group attached phenyl
ammonium triflates afforded moderate to good yields of the
desired products (5a−5d), although an electron-donating
group slightly affected the efficiency (5c). α- and β-silylated
naphthenes could be synthesized with high yields from
corresponding ammonium triflates (5e and 5f), and 78%
yield of 5e could be produced with 1 mmol scale synthesis.
The para-substitution of electron-withdrawing groups (F3C−,
NC−, and MeO2S−) had no obvious effect on the reaction
(5g−5i). Moderate to good yields were obtained with diverse
alkyl or aryl group contained esters (5j−5l), while a lower
reaction temperature was employed to achieve satisfactory
yields in some cases (5i, 5k, and 5l). Heterocycle-installed aryl
ammonium triflates were also eligible substrates for silylation.
Carbazole-attached substrate gave the desired product 5m in
Recently, base-mediated silylation of the sp2 C−H or C−F
bond unraveled simple and environmentally benign pathways
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Letter
a
Scheme 3. Scope of Arylammonium Salts
Scheme 4. Further Investigation
(Scheme 4c). Benzylic ammonium salt 6 bearing I− produced
the desired product 3a with 54% isolated yield.
To explore a simple way for late-stage functionalization of
amines, one-pot borylsilylation of N,N-dimethylbenzylamine 7
was conducted (Scheme 4d). MeOTf was employed to react
with 7 in toluene at room temperature first to promote
methylation. After 3 h, to this mixture cooled to 0 °C were
added the silylborane 2a and KHMDS sequentially. The
product 3a was obtained with 60% yield after 3 h. A similar
procedure was applied successfully in the one-pot silylation of
p-phenylaniline 8 in THF. The product 5a was isolated in 68%
yield after 12 h at 55 °C (Scheme 4e). Furthermore, our
methodology exhibited significant advantages for installing two
different silyl groups in phenyl ring (Scheme 4f). First, the
Ph2MeSi− group was easily incorporated by B(C6F5)3-
catalyzed silylation of aniline with 76% yield.17 Then one-pot
base-mediated ipso silylation conditions were employed, and
5aa bearing two different silyl units previously unattainable was
produced with 66% yield.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), LiOtBu (0.4
mmol, 2.2 M in THF), THF (0.5 mL), 55 °C, 12 h, isolated yields.
The possible mechanism is depicted in Scheme 5. Relevant
literature18 has demonstrated that the combination of base and
b
c
25 °C. 1 (0.4 mmol), 2a (0.2 mmol), 25 °C, 12 h.
Scheme 5. Proposed Mechanism
94% yield. Indole, pyrrole, and furan groups which could be
silylated with silane and KOtBu16 were compatible in our
system (5n−5q), and ipso-silylation occurred exclusively with
moderate to good yields. A silyl group could be incorporated
smoothly into the base-sensitive isoxazole-containing molecule
(5r). The sulfonamide group remained intact in the synthesis
of 5s with a 52% yield. The substrate scope could be extended
to CC bond-containing substrate, although excess ammo-
nium salts were used to suppress the side reactions (5t, 5u).
Silyl unit installed substrate reacted well with silylborane to
afford 5v with 60% yield. p-tert-Butyl- and m-methyl-
substituted substrates showed inferior reactivity, only giving
the targeted products with approximately 40% yields (5w−5y).
The reactivity of benzylic and aryl ammonium salts with
Et3Si-Bpin was explored (Scheme 4a,b). Only 53% yield of 3v
and 32% yield of 5z were obtained from the corresponding
starting materials 1i and 4e, much lower than the reactions of
PhMe2Si−Bpin. The influence of counterions was next tested
silylborane could generate the anionic boron species A along
with the silyl anion B. In the presence of substrate 1, benzylic
deprotonation occurred to form the intermediate C. Then 1,2-
migration of the silyl group from boron to carbon and release
of the ammonium group proceeded to afford the product 3.
When substrate 4 was used, nucleophilic attack of silyl anion B
to the aryl group of 4 happened to furnish product 5 by ipso
substitution.15 Based on this mechanism, we tried to synthesize
chiral gem-silylboronates using nBuLi and (−)-sparteine.9c
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Letter
However, no product was detected under various reaction
conditions, probably because of the steric hindrance of the
bulky chiral base.
mental Research Funds for the Central Universities, Sun Yat-
sen University (20ykpy129). This work was also sponsored by
MOE Key Laboratory of Laser Life Science.
In summary, the base-mediated borylsilylation/silylation of
ammonium salts has been achieved under mild reaction
conditions. Diverse gem-silylboronates and aryl silanes have
been synthesized with good efficiency. The easy-to-handle
procedures and good functional group-tolerance proved the
practicality and convenience of this methodology for late-stage
functionalization of amines.
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AUTHOR INFORMATION
Corresponding Authors
■
Guohai Liang − MOE Key Laboratory of Laser Life Science &
Institute of Laser Life Science, College of Biophotonics, South
China Normal University, Guangzhou 510631, China;
Email: liangguoh@scnu.edu.cn
Yong Luo − School of Pharmaceutical Science (Shenzhen),
Sun Yat-sen University, Guangzhou 510275, China;
orcid.org/0000-0002-8217-5677; Email: luoyong5@
mail.sysu.edu.cn
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Authors
Wan-Ying Qi − School of Pharmaceutical Science (Shenzhen),
Sun Yat-sen University, Guangzhou 510275, China
Jing-Song Zhen − School of Pharmaceutical Science
(Shenzhen), Sun Yat-sen University, Guangzhou 510275,
China
Xiao-hong Xu − School of Pharmaceutical Science (Shenzhen),
Sun Yat-sen University, Guangzhou 510275, China
Xian Du − School of Pharmaceutical Science (Shenzhen), Sun
Yat-sen University, Guangzhou 510275, China
Yi-hui Li − School of Pharmaceutical Science (Shenzhen), Sun
Yat-sen University, Guangzhou 510275, China
Han Yuan − School of Pharmaceutical Science (Shenzhen),
Sun Yat-sen University, Guangzhou 510275, China
Yun-Shi Guan − School of Pharmaceutical Science
(Shenzhen), Sun Yat-sen University, Guangzhou 510275,
China
Xun Wei − School of Pharmaceutical Science (Shenzhen), Sun
Yat-sen University, Guangzhou 510275, China
Zi-Ying Wang − School of Pharmaceutical Science
(Shenzhen), Sun Yat-sen University, Guangzhou 510275,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02066
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the National Natural
Science Foundation of China (21901260) and the Funda-
■
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