Palladium-Catalyzed Amide N-C Hiyama Cross-Coupling: Synthesis of Ketones

Article abstract of DOI:10.1021/acs.orglett.0c03260

N-Acylglutarimides and arylsiloxanes reacted in the presence of Pd(OAc)2/PCy3, Et3N·3HF, and LiOAc to provide the corresponding arylketones in good yields. Aryl-, vinyl-, and alkyl-substituted N-acylglutarimides showed good activity in the coupling reactions of arylsiloxanes. The reaction had a broad substrate scope and showed good functional group tolerance. N-Benzoylsuccinimide and N-protected N-phenylbenzamides showed good activities in coupling reactions with phenylsiloxane. The employment of CuF2 as an activor afforded the decarbonylative products at 160 °C.

Full text of DOI:10.1021/acs.orglett.0c03260

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Amide N−C Hiyama Cross-Coupling: Synthesis
of Ketones
Muhammad Aliyu Idris and Sunwoo Lee*
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ABSTRACT: N-Acylglutarimides and arylsiloxanes reacted in the
presence of Pd(OAc)2/PCy3, Et3N·3HF, and LiOAc to provide the
corresponding arylketones in good yields. Aryl-, vinyl-, and alkyl-
substituted N-acylglutarimides showed good activity in the coupling
reactions of arylsiloxanes. The reaction had a broad substrate scope and
showed good functional group tolerance. N-Benzoylsuccinimide and N-
protected N-phenylbenzamides showed good activities in coupling
reactions with phenylsiloxane. The employment of CuF2 as an activor
afforded the decarbonylative products at 160 °C.
Scheme 1. Coupling of Amides and Carbon Nucleophiles
he amide functionality is one of the most important
structures in nature because peptides, the key compo-
T
nents of proteins and enzymes, consist of an amide backbone.1
In addition, amide moieties have been widely utilized as
building blocks for various materials owing to the robust
nature of the amide C−N bond. In recent years, amide C−N
bond cleavage has received considerable attention for the
transformation of amides to carbonyl compounds, including
other amides.
Transamidation, which is the transformation of one amide to
another, has been reported by numerous groups. Stahl
reported that amides reacted with amines in the presence of
Lewis acids such as Zr, Al, and Sc to provide thermodynamic
equilibrium mixtures.2 The use of palladium or nickel catalysts
afforded the desired transamidated products as the major
products in reactions between amides and amines.3 Transition-
metal-catalyst-free transamidations were also reported by
several groups.4 Very recently, the Szostak group demonstrated
that a variety of unactivated tertiary amides could be
transformed to other amides in the presence of LiHMDS.5
Amide C−N activation has likewise been employed for
reactions with oxygen and carbon nucleophiles. Amide to ester
transformations employing transition-metal catalysts such as
nickel and zinc, as well those proceeding under metal-free
conditions, have been reported by several groups.6
The reaction of amides and carbon nucleophiles in the
presence of transition-metal catalysts provides ketones. Various
carbon nucleophiles can be employed for this purpose. Suzuki
cross-coupling between amides and arylboron compounds has
been independently reported by Garg, Huang, Jian, Rueping,
Szostak, Zeng, and Zou (Scheme 1a).7 It has been reported
that Suzuki decarbonylative coupling products were formed
when the reaction was conducted at high temperature.8
Arylzinc compounds, which are coupling partners in Nigeshi
cross-coupling, have also been employed in reactions with
amides for the synthesis of ketones, as reported by Garg and
Szostak.9 Grignard reagents have been utilized for coupling
reactions with amides by the Kandasamy group to generate
ketones. Very recently, the Szostak group also reported the
coupling with amide and Grignard reagents.10 Zheng reported
that palladium-catalyzed Sonogashira coupling of amides
Received: September 28, 2020
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© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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provided alkynyl ketones.11 Han reported that nickel-catalyzed
reductive N−C coupling of amides and aryl iodides provides
diarylketones12 (Scheme 1b). Recently, we reported a nickel-
catalyzed Claisen condensation-type coupling reaction be-
tween two different amides for the construction of new C−C
bonds.13 In addition, we demonstrated that an enolizable
ketone functions as a carbon nucleophile, reacting with amides
under transition-metal-free conditions to provide 1,3-diketones
in good yields14 (Scheme 1c).
However, to the best of our knowledge, there are no reports
on the use of arylsilanes as nucleophiles in coupling reactions
with amides. Numerous methods for the synthesis of
arylsilanes have recently been developed.15 Therefore,
arylsilanes would be favorable coupling partners for the
formation of ketones via C−N activation of amides. Herein,
we report palladium-catalyzed Hiyama-type amide coupling
reactions for the synthesis of the corresponding ketones
(Scheme 1d).
dppb, dppf, and Xantphos provided 3aa in 30%, 45%, 40%, and
35% yields, respectively (entries 3−6). When the reactions
were conducted with Pd(dba)2 and Pd(CH3CN)2Cl2, 3aa was
formed in 15% and 68% yields, respectively (entries 7 and 8).
The use of Pd(PCy3)2Cl2 resulted in 85% yield, comparable to
the result of the Pd(OAc)2/PCy3 reaction (entry 9). Reactions
performed in the absence of H2O led to a low yield of 3aa
(entry 10). When the reactions were performed in THF and
toluene, 3aa was obtained in 35% and 50% yields, respectively
(entries 11 and 12). Reactions carried employing TBAF and
Py·HF as activators provided 3aa in 2% and 20% yields,
respectively (entries 13 and 14). Reactions with KOAc or
NaOAc delivered lower yields than did the reactions with
LiOAc (entries 15 and 16). Reducing the amount of Pd/L to 1
mol %, decreasing the reaction temperature to 50 °C, and
shortening the reaction time to 3 h resulted in the formation of
3aa in 65%, 58%, and 70% yields, respectively (entries 17−19).
When the reaction was conducted at 160 °C in the sealed tube
reactor, 3aa was formed in 84%, however, the decarbonylative
product was not detected in the reaction mixture (entry 20).
With the optimized conditions in hand, as shown in Scheme
2, we evaluated a variety of substituted N-benzoylglutarimides
in the coupling reaction with phenyltriethoxysilane. N-
Benzoylglutarimides bearing alkyl groups such as methyl and
tert-butyl afforded the corresponding ketones 3aa, 3ba, and
3da in good yields. However, o-methyl-substituted N-
benzoylglutarimide 1c gave a relatively low product yield due
to increased steric hindrance in the substrate. N-Benzoylglutar-
imide provided benzophenone in 92% yield. Methoxy-
substituted N-benzoylglutarimides provided the corresponding
ketones 3fa, 3ga, and 3ha in 57%, 94%, and 92% yields,
respectively. N-Acylglutarimides bearing biphenyl and naph-
thyl groups provided the desired ketones, with ortho-
substituted products (3ia and 3la) being formed in lower
yields than their counterparts. Monofluoro- and difluoro-
substituted N-benzoylglutarimides afforded the corresponding
fluorinated benzophenones in moderate to good yields. 4-
Trifluoromethyl-, 4-chloro-, and 2-chloro-N-benzoylglutari-
mides provided 3qa, 3ra, and 3sa in 83%, 67%, and 96%
yields, respectively. N-Benzoylglutarimides bearing electron-
withdrawing substituents such as nitro, cyano, ketone, and
aldehyde afforded the corresponding ketones in moderate to
good yields. 2- and 3-furanyl-substituted N-acylglutarimides
furnished 3xa and 3ya in 73% and 70% yields, respectively. N-
Acylglutarimides with α,β-unsaturated, cyclic, and straight-
chain alkyl groups provided the corresponding ketones 3za,
3a′a, and 3b′a in 45%, 75%, and 72% yields, respectively.
However, N-acylglutarimide having a sterically bulky alkyl
group such as tert-butyl did not give the desired coupling
product 3c′a.
N-4-Methylbenzoylglutarimide and triethoxyphenylsilane
were chosen as model substrates to determine the optimal
cross-coupling conditions (Table 1). After an intensive
Table 1. Optimization of Conditions for the Hiyama
a
Coupling of 1a and 2a
b
entry
deviation from the standard conditions
none
no Pd(OAc)2/PCy3
yield (%)
1
2
87
0
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
PPh3 instead of PCy3
dppb instead of PCy3
dppf instead of PCy3
30
45
40
35
15
68
85
40
35
50
trace
20
72
55
65
58
70
84
Xantphos instead of PCy3
Pd(dba)2 instead of Pd(OAc)2
Pd(CH3CN)2Cl2 instead of Pd(OAc)2
Pd(PCy3)2Cl2 instead of Pd(OAc)2/PCy3
no H2O
THF instead of 1,4-dioxane/H2O
toluene instead of 1,4-dioxane/H2O
TBAF instead of Et3N·3HF
Py·HF instead of Et3N·3HF
KOAc instead of LiOAc
NaOAc instead of LiOAc
1 mol % Pd and L instead of 2 mol %
50 °C instead of 90 °C
3 h instead of 6 h
160 °C instead of 90 °C
Next, 4-methylphenyl-, 4-methoxyphenyl-, 4-chlorophenyl-,
and 2-thiophene-yltriethoxysilanes (2b, 2c, 2d, and 2e) were
evaluated in the coupling reaction with N-4-methylbenzoyl-
glutarimide, N-benzoylglutarimide, N-4-methoxybenzoylglutar-
imide, and N-4-fluorobenzoylglutarimide (1a, 1e, 1h, and 1o)
under the optimized conditions. In addition, the synthesis and
the late-stage modification of biologically active compounds
were conducted by using this methodology. The results are
summarized in Scheme 3. All reactions afforded the
corresponding ketones in good yields. When alkyl-substituted
triethoxysilanes such as n-octyltriethoxysilane (2f) and cyclo-
pentyltriethoxysilane (2g) were allowed to react with N-4-
nitrobenzoylglutarimide (1t), no coupled products were found.
a
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), Pd(OAc)2
(0.006 mmol), PCy3 (0.012 mmol), Et3N·3HF (0.6 mmol), and
LiOAc (0.3 mmol) were reacted in 1,4-dioxane/H2O (0.5 mL/0.5
b
1
mL) at 90 °C for 6 h. Determined by gas chromatography and H
NMR spectroscopy with an internal standard.
evaluation of various reaction conditions, we established that
Pd(OAc)2 and PCy3 in 1,4-dioxane/H2O afforded the desired
product 3aa in 87% yield in the presence of Et3N·3HF and
LiOAc (entry 1). When the reaction was performed in the
absence of Pd(OAc)2, the coupling product was not obtained
(entry 2). Reactions with phosphine ligands such as PPh3,
B
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Scheme 2. Hiyama Coupling of Various Substituted N-
Acylglutarimides and 2a
Scheme 3. Hiyama Coupling of Substituted N-
a
a
Acylglutarimides and Arylsiloxanes
a
Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), Pd(OAc)2 (0.02
mmol), PCy3 (0.04 mmol), Et3N·3HF (2.0 mmol), and LiOAc (1.0
mmol) were reacted in 1,4-dioxane/H2O (1.5 mL/1.5 mL) at 90 °C
for 6 h. Numbers in parentheses represent isolated yields.
a
Scheme 4. Hiyama Coupling of Various Amides and 2a
a
Reaction conditions: 1 (1.0 mmol), 2a (1.5 mmol), Pd(OAc)2 (0.02
mmol), PCy3 (0.04 mmol), Et3N·3HF (2.0 mmol), and LiOAc (1.0
mmol) were reacted in 1,4-dioxane/H2O (1.5 mL/1.5 mL) at 90 °C
for 6 h. The numbers in parentheses represent isolated yields.
a
Reaction conditions: 1 (1.0 mmol), 2a (1.5 mmol), Pd(OAc)2 (0.02
mmol), PCy3 (0.04 mmol), Et3N·3HF (2.0 mmol), and LiOAc (1.0
mmol) were reacted in 1,4-dioxane/H2O (1.5 mL/1.5 mL) at 90 °C
for 6 h. Numbers in parentheses represent isolated yields.
Fenofibrate (3d′d),16 which is used to treat primary hyper-
cholesterolemia, was formed in 45% yield. In addition,
probenecide was employed for the last-stage modification.17
It was converted to the corresponding 4-N,N-dipropylsulfona-
midobenzoylglutarimide and coupled with 1a to give the 3e′a
in 61% yield.
was employed at 160 °C. However, as shown in eq 1, the
maximum yield was 30%.
To study the influence of the amide structural properties on
the reaction, various benzamides were reacted with phenyl-
triethoxysilane under the optimized conditions (Scheme 4). N-
Benzoylsuccinimide reacted with 2a smoothly to give 3ea in
85% yield. However, N-benzoylsaccharin did not produce the
desired product. N-Tosyl- and N-Boc-protected N-phenyl-
benzamides provided 3ea in 91% and 43% yields, respectively.
Unfortunately, unactivated tertiary amides such as N-methyl-
N-phenylbenzamide were not active in this coupling reaction.
It was found that 1−2 and 1−5 did not give the desired
product even at 150 °C with 10 mol % catalyst.
To elucidate the electronic effects of the substituents and
reaction pathways, several control experiments were conducted
(Scheme 5). When equal amounts of 1h and 1t were reacted
with 2a under standard conditions, the corresponding ketones
3ha and 3ta were formed in 5% and 84% yields, respectively.
Equal amounts of 2c and 2d were treated with 1e under
standard conditions to deliver 3ec and 3ed in 45% and 25%
It was noteworthy that we found that the Hiyama
decarbonylative coupling products were formed when CuF2
C
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Scheme 5. Control Experiments
Scheme 6. Proposed Mechanism
In summary, N-acylglutarimides reacted with arylsiloxanes to
provide the corresponding arylketones via amide C−N bond
cleavage. It was established that Pd(OAc)2/PCy3 showed the
highest activity in the presence of Et3N·3HF and LiOAc. The
reaction featured broad functional group tolerance, with a
variety of substituted N-benzoylglutarimides and N-alkylacyl-
glutarimides providing the corresponding ketones in good
yields. N-Benzoylsuccinimide and N-protected N-phenyl-
benzamides reacted with phenylsiloxane to give arylketone
products in good yields. This is the first example of a Hiyama-
type coupling reaction involving amides, which proceeds via an
ionic reaction pathway. Further studies to elucidate the
detailed reaction mechanisms are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge at
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yields, respectively. These results imply that N-benzoylglutar-
imides with electron-withdrawing substituents provided higher
activities than those with electron-donating substituents. In
contrast, electron-donating substituents in triethoxylphenyl
silanes led to higher yields than those obtained with electron-
withdrawing substituents. The competitive reaction between
1a and 1−3 provided 3aa and 3ea in 72% and 15% yields,
respectively. This result implies that N-benzoylglutarimide is
higher reactive than N-phenyl-N-tosylbenzamide. When two
amides 1a and 1−3 were treated with Pd(OAc)2/PCy3 and
LiOAc in the absence of Et3N·3HF and PhSi(OEt)3, only 1a
was converted to the palladium complex. This result supports
that the oxidative addition step of 1a might be faster than that
of 1−3. When the reaction of 1e and 2a was conducted in the
presence of 2 equiv of BHT or TEMPO, the desired product
was formed in 68% and 80% yields, respectively. These results
indicate that the reaction proceeds via an ionic mechanism.
Based on our experimental results and previous reports on
amide coupling reactions, we propose a plausible reaction
mechanism, as shown in Scheme 6. Pd(0) is oxidatively added
to the amide C−N bond to provide palladium complex A.
Arylsiloxane is activated by the fluoride anion of Et3N·3HF to
give activated arylsiloxane B, followed by the exchange of aryl
and glutarimide to afford palladium complex C. Reductive
elimination of C finally produces the desired ketone and
regenerates Pd(0).
Experimental procedures and spectral data for the
products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Sunwoo Lee − Department of Chemistry, Chonnam National
University, Gwangju 61186, Republic of Korea; orcid.org/
0000-0001-5079-3860; Email: sunwoo@chonnam.ac.kr
Author
Muhammad Aliyu Idris − Department of Chemistry, Chonnam
National University, Gwangju 61186, Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03260
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korean
government (MSIP) (NRF-2017R1A2B2002929). The spec-
tral and HRMS data were obtained from the Korea Basic
Science Institute, Gwangju Center and Daegu Center.
D
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