Palladium-Catalyzed C-H Silylation of Aliphatic Ketones Using an Aminooxyamide Auxiliary

Article abstract of DOI:10.1021/acs.orglett.1c01678

A palladium-catalyzed β-C(sp3)-H silylation of aliphatic ketones with disilanes to afford β-silyl ketones is reported. The aminooxyamide auxiliary is critical for the C-H activation and silylation. The reaction tolerates a number of functional groups and

Full text of DOI:10.1021/acs.orglett.1c01678

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Letter
Palladium-Catalyzed C−H Silylation of Aliphatic Ketones Using an
Aminooxyamide Auxiliary
Jianhua Li and Chao Jiang*
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ABSTRACT: A palladium-catalyzed β-C(sp3)−H silylation of
aliphatic ketones with disilanes to afford β-silyl ketones is reported.
The aminooxyamide auxiliary is critical for the C−H activation and
silylation. The reaction tolerates a number of functional groups and
shows good selectivity in silylating β-C(sp3)−H bonds in the
company of C(sp2)−H bonds and acidic α-C(sp3)−H bonds. The
reaction is scalable, and the aminooxyamide auxiliary is readily
removed to give β-silyl ketones, which could serve as useful building blocks for organic synthesis. Late-stage diversification using this
protocol is demonstrated in the silylation of santonin with good yield.
Scheme 1. Palladium-Catalyzed C(sp3)−H Silylation and
rganosilicon compounds have distinct chemical and
physical character that endows them an important role
C(sp3)−H Functionalization of Ketones
O
in organic synthesis,1 material science,2 and medicinal
chemistry.3 Transition-metal-catalyzed direct and selective
aliphatic C(sp3)−H silylation is of great value in accordance
with atom and step economy. Thus, plenty of efforts have been
devoted to develop new methodologies in this respect during
the past decades. Significant advances have been made in
transition-metal-catalyzed reactions using Ru, Rh, Ir, and Pt as
catalysts.4 Compared with the reported palladium-catalyzed
C(sp2)−H silylation,5 palladium-catalyzed direct silylation of
aliphatic C(sp3)−H bonds remains a great challenge.6 The
strategy employing directing-group assistance was proved to be
crucial for the intermolecular silylation of unactivated aliphatic
C−H bonds. Since the pioneering work by the Kanai group,7
an 8-aminoquinoline auxiliary was successfully employed in the
palladium-catalyzed β-C(sp3)−H silylation of aliphatic carbox-
ylic acids and amino acids8,9 (Scheme 1a) and later in the γ-
C(sp3)−H silylation of aliphatic carboxylic acids.10 Moreover,
oxalyl amide assisted benzylic silylation of amine derivatives11
and picolinamide assisted γ-C(sp3)−H silylation of peptides
were also developed.12 As far as we know, direct silylation of
distal C(sp3)−H bonds of aliphatic ketones has never been
reported.
The direct functionalization of unactivated C−H bonds of
ketones will expand their synthetic applications and provide
new synthetic disconnections, as ketones are widely present in
bulk chemicals, synthetic building blocks, and natural products.
Oxime-directed β-C(sp3)−H acetoxylation, arylation and
amination of ketones,13 β-C(sp3)−H arylation of ketones or
aldehydes using a transient directing group,14 as well as β-
C(sp3)−H iodination and arylation of ketones using a practical
aminooxyacetic acid auxiliary (Scheme 1b)15 have been
reported. However, the direct C(sp3)−H functionalization of
ketones16 has been highly limited in both the types of
transformations and the scope of substrates. Inspired by Yu’s
recent work using the L, X-type aminooxyacetic acid auxiliary15
to facilitate catalytic C−H functionalizations of aliphatic
Received: May 18, 2021
Published: June 29, 2021
https://doi.org/10.1021/acs.orglett.1c01678
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5359−5362
5359

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Letter
a b
,
ketones, we have developed the palladium-catalyzed direct β-
C(sp3)−H silylation of aliphatic ketones. The resulting β-silyl
ketones would serve as useful building blocks for organic
synthesis.
Table 2. Scope of Methyl and Alkyl Ketones
Pinacolone was chosen as the model substrate in our study,
and an oxime auxiliary was installed (Table 1). To our delight,
a b
,
Table 1. Optimization Studies
a
Conditions: substrate (0.1 mmol, 1.0 equiv), Pd(OAc)2 (10 mol %),
Cu(OAc)2·H2O (10 mol %), (SiMe3)2 (2.5 equiv), AgTFA (3.0
equiv), Li2CO3 (2.0 equiv), toluene (2.0 mL), under air, at 110 °C for
b
c
6 h. Isolated yields. The C(sp2)−H silylation product (2h′) was
observed in 14% yield.
a
the aminooxyamide moiety were compatible under the
silylation conditions, and no C(sp2)−H silylation was observed
(2b−2e). Ketone derived from Gemfibrozil was silylated at the
β-methyl group with 72% yield (2e). A variety of functional
groups, including ester, chlorine, and alkene substituents, were
well tolerated (2f−2h, 2j, 2l). No α-silylation happened with
the acidic α-hydrogen; only β-C(sp3)−H silylation products
were isolated (2j). For alkenyl ketone, β-C(sp3)−H silylation
product was obtained in 57% yield (2h) with an inseparable
minor C(sp2)−H silylation product in 14% yield (2h′).
Notably, cyclobutyl substituted ketone was β-silylated at the
methylene C−H bond in 62% yield (2i).
The scopes of aryl (2m−2s), heteroaryl (2t), and styrenyl
(2u−2y) ketones were also investigated (Table 3). Aryl
ketones with electron-donating groups, including methoxyl,
methyl, and tert-butyl groups, or halogen groups, including
fluorine and chlorine, were compatible under the silylation
conditions (2m−2s). Heteroaryl ketone containing thiophene
was tolerated (2t). Styrenyl ketones with electron-withdrawing
groups, such as cyano and nitro groups, or fluorine, were
tolerated (2u−2y). Notably, no C(sp2)−H silylation was
observed in these ketones containing phenyl or alkenyl
C(sp2)−H bonds.
Conditions: 1a (0.1 mmol, 1.0 equiv), Pd(OAc)2 (10 mol %),
Cu(OAc)2·H2O (20 mol %), (SiMe3)2 (2.5 equiv), AgTFA (3.0
equiv), Li2CO3 (2.0 equiv), toluene (2.0 mL), 110 °C, under air, 6 h.
b
1
Yield determined by H NMR analysis of the crude product using
1,3,5-trimethoxybenzene as the internal standard. The yield in
parentheses is the isolated yield.
after extensive screening of various reaction parameters, the
desired silylated product 2a was obtained in 73% yield (72%
isolated yield) using Pd(OAc)2 (10 mol %), Cu(OAc)2·H2O
(20 mol %), hexamethyldisilane (2.5 equiv), AgTFA (3.0
equiv), and Li2CO3 (2.0 equiv) in toluene (2 mL) at 110 °C
for 6 h with the aminooxyamide auxiliary DG1 (entry 1). Other
types of carboxylic acid auxiliaries such as DG2 and DG3,
which were employed in the C(sp3)−H iodination and
arylation of ketones,15 or amide auxiliary DG4, all gave poor
yields (entries 2−4). Using other inorganic bases than Li2CO3,
the yield of silylated products decreased (entries 5−7). The
reaction became less efficient without Cu(OAc)2·H2O and
with other copper salts (entries 8−10). The yield decreased at
other temperatures (entries 11−13).
With the optimal auxiliary and reaction conditions
discovered, we explored the scope of ketones using
hexamethyldisilane as the silylation partner. We continued
the studies with various methyl (2a−2i) and alkyl (2j−2l)
ketones (Table 2). Alkyl substituted ketones were β-silylated in
good to excellent yields (2a, 2i, 2k). Aromatic moieties trans to
Removal of the aminooxyamide auxiliary was achieved by
reacting the silylation products with 4 M HCl in 1,4-dioxane
and water at 80 °C, delivering β-silylated ketone (3d) in 73%
yield (Scheme 2a). To further demonstrate the synthetic value
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a b
,
bioactive molecules makes the silylation a practical method for
late-stage diversification. Thus, direct C(sp3)−H silylation of
santonin was performed to provide its potentially useful
silylated analogue 2z in 73% yield (Scheme 2c).
Table 3. Scope of Aryl, Heteroaryl, and Styrenyl Ketones
In summary, C(sp3)−H silylation of aliphatic ketones was
developed using an aminooxyamide auxiliary. Broad substrate
scope and selectivity for aliphatic ketones and the application
for late-stage C(sp3)−H functionalizations have been revealed.
This reaction also features facile installation and removal of the
auxiliary. Further studies of silylation of other challenging C−
H bonds in aliphatic ketones, such as γ-methyl or methylene
C−H bonds, are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01678.
Additional screening tables, detailed experimental
procedures, compound characterization data, and
NMR spectra of all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Chao Jiang − School of Chemistry and Chemical Engineering,
Nanjing University of Science and Technology, Nanjing,
Jiangsu 210094, China; orcid.org/0000-0002-9228-
1924; Email: chaojiang@njust.edu.cn
a
Conditions: substrate (0.1 mmol, 1.0 equiv), Pd(OAc)2 (10 mol %),
Cu(OAc)2·H2O (10 mol %), (SiMe3)2 (2.5 equiv), AgTFA (3.0
equiv), Li2CO3 (2.0 equiv), toluene (2.0 mL), under air, at 110 °C for
Author
b
6 h. Isolated yields.
Jianhua Li − School of Chemistry and Chemical Engineering,
Nanjing University of Science and Technology, Nanjing,
Jiangsu 210094, China
Scheme 2. Auxiliary Removal, Gram-Scale Reaction, and
Late-Stage C(sp3)−H Silylation of Santonin
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01678
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science
Foundation of China (NSFC) (Grant No. 21772092).
■
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