A Strategy for Amide C-N Bond Activation with Ruthenium Catalyst: Selective Aromatic Acylation

Article abstract of DOI:10.1021/acs.orglett.1c00464

A strategy for amide C-N bond activation with ruthenium catalyst is described for the first time. The in situ formed bis-cycloruthenated complexes were demonstrated to be the key active species with superior oxidative addition ability to an inert amide C-N bond. The direct C-H bond activation of 2-arylpyridines followed by the amide C-N bond activation took place in the presence of a ruthenium precatalyst to produce monoacylation products in moderate to good yields. Synthetically useful functional groups, such as halogen atoms (F and Cl), ester, acetyl, and vinyl, remained intact during tandem C-H/C-N bond activation reactions.

Full text of DOI:10.1021/acs.orglett.1c00464

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Letter
A Strategy for Amide C−N Bond Activation with Ruthenium Catalyst:
Selective Aromatic Acylation
Wenkuan Li, Sheng Zhang,* Xiujuan Feng, Xiaoqiang Yu, Yoshinori Yamamoto, and Ming Bao*
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ABSTRACT: A strategy for amide C−N bond activation with ruthenium
catalyst is described for the first time. The in situ formed bis-cycloruthenated
complexes were demonstrated to be the key active species with superior
oxidative addition ability to an inert amide C−N bond. The direct C−H
bond activation of 2-arylpyridines followed by the amide C−N bond
activation took place in the presence of a ruthenium precatalyst to produce monoacylation products in moderate to good yields.
Synthetically useful functional groups, such as halogen atoms (F and Cl), ester, acetyl, and vinyl, remained intact during tandem C−
H/C−N bond activation reactions.
cost-effectiveness, good compatibility with commonly used
oxidants, and stability in air and moisture,12 no successful
example of using Ru catalysts has been reported to date. The
reason may be ascribed to the weak capacity of Ru catalysts in
oxidative addition reactions with an electrophile.
ransition metal (TM)-catalyzed amide C−N bond
Tactivation has recently become an interesting topic in
organic synthesis.1 After the pioneering works of Garg2 and
Szostak3 in 2015, many contributions have been made in this
field by other researchers, including Rueping,4 Stanley,5 Shi,6
Zou,7 Zeng,8 and Han.9 Hong and co-workers recently
reported a dual-photoredox nickel catalytic system for amide
C−N bond activation.10 The readily available and inexpensive
but inert amides have been successfully employed as
electrophilic reagents in an acylation or alkylation reaction
via the release of carbon monoxide through ground state
destabilization achieved by modifying the stereoelectronic
characters of amides.11 To the best of our knowledge, only
three TMs, namely, palladium (Pd), nickel (Ni), and rhodium
(Rh), can be used as catalysts in amide C−N bond activation
(Figure 1a). Although ruthenium (Ru) catalysts usually have
In comparison, Ru-catalyzed C−H bond activation has been
well-studied,13 and [RuCl2(p-cymene)]2 has been proven to be
a versatile precatalyst for direct C−H functionalization.14
Among the substrates used, 2-arylpyridines are more frequently
utilized as the starting materials in Ru-catalyzed C−H
functionalization.15 Importantly, it was clearly demonstrated
that cyclometalated Ru catalysts possess superior catalytic
activity compared to commonly employed Ru species.16 On
the basis of previous work, we hypothesized that the
cycloruthenated species generated in situ from 2-arylpyridines
may undergo oxidative addition reaction with amides because
of their enhanced activities and ultimately offer acylation
products through reductive elimination. As expected, the
desired C−H acylation products were obtained when 2-
arylpyridines were treated with amides as acylating reagents in
the presence of a Ru catalyst (Figure 1b). The first C−H bond
functionalization with amides by double C−H/C−N bond
activation using Rh catalyst has recently been reported by
Meng and Szostak.17 Unlike previous reported precious
catalytic systems, this is the first example of Ru-catalyzed
amide C−N bond activation. The results are reported in this
paper.
Received: February 7, 2021
Published: March 12, 2021
Figure 1. Amide C−N bond activation with TM catalysts.
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In our initial studies, the reaction of 2-phenylpyridine (1a)
and N-phenyl-N-tosylbenzamide (2a) was chosen as the model
to optimize the reaction conditions for amide C−N bond
activation using [RuCl2(p-cymene)]2 and K2CO3 as the
precatalyst and base, respectively. The results are summarized
in Table 1. The desired ortho-acylated product 3aa was
formation of acylation product 3aa in higher yield than those
obtained using other ligands (entry 16 vs entries 13 and 14).
Although the yield of 3aa was successfully increased to 70% by
the combined use of MesCO2H and PCy3 in acetone, the
generation of a trace amount of byproduct mesityl(2-(pyridin-
2-yl)phenyl)methanone was also detected. To our delight, the
formation of a byproduct can be completely suppressed by
utilizing a sterically hindered acid, such as 2,4,6-triisopropyl-
benzoic acid (TIPBA), as the additive instead of MesCO2H
(entry 17, 72% yield). Further investigation revealed that the
ligand tri-p-tolylphosphane [P(p-Tol)3] gave the same effect as
PCy3 (entry 17 vs entry 18). The reactivities of other activated
amides, such as N-(tert-butyloxycarbonyl)-N-benzylbenzamide
(2ab), N,N-di(tert-butyloxycarbonyl) benzamide (2ac), and 1-
benzoylpiperidine-2,6-dione (2ad), were also investigated.
Diminished or no reactivity was observed under the optimal
reaction conditions (Scheme 1).
Table 1. Optimization of Reaction Conditions for Ru-
a
Catalyzed C−H/C−N Activation
b
Entry
Solvent
Additive
Ligand
Yield (%)
25
NR
1
2
3
4
5
6
toluene
DCE
THF
dioxane
DMF
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
AcOH
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PPh3
c
15
32
trace
35
39
40
24
45
45
47
64
51
36
70
72
72
Scheme 1. Reactivities of Different Activated Amides
tBuOH
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
7
8
9
TFA
PivOH
10
11
12
13
14
15
16
17
18
1-AdCO2H
PhCO2H
MesCO2H
MesCO2H
MesCO2H
MesCO2H
TIPBA
The scope and limitation of this type of aromatic C−H bond
direct acylation reaction were determined under the optimal
reaction conditions. First, the scope of 2-arylpyridines was
investigated using 2a as the reaction partner. The results are
shown in Table 2. Similarly, the reactions of para-substituted
2-phenylpyridines (1b−1l) proceeded as smoothly as the
reaction of 1a to produce the ortho-acylated products 3ab−3al
in satisfactory to good yields (60%−84%). These results
revealed that the electronic property (electron-donating or
electron-withdrawing) of the substituent linked to the benzene
ring did not exert a remarkable influence on the reactivity of 2-
arylpyridines. Synthetically useful functional groups, such as
vinyl, fluorine, methoxycarbonyl, and acetyl, linked to the
benzene rings of substrates 1i−1l were maintained in the
structures of products 3ai−3al. This finding suggests that
further manipulation may produce additional useful com-
pounds. Interestingly, acylation and aldol condensation
simultaneously occurred to produce unexpected product 3am
when the substrate 1m, which bears a formyl group on the
para-position, was examined in acetone. No reaction was
observed when a 2-arylpyridine substrate with an ortho-
substituent on the benzene ring was tested under the optimal
reaction conditions; the reason may be attributed to the steric
hindrance caused by the ortho-substituent. The results
obtained by further investigation indicated that a substituent
linked on the pyridine ring of 2-arylpyridine also did not
influence reactivity. The desired products 3an−3ar were
obtained in high to good yields (69%−85%). As expected,
the reaction of naphthalene ring-containing substrate 1s also
proceeded smoothly to furnish the corresponding product 3as
in 65% yield. Although the desired product 3at was collected in
relatively low yield (52%), the result obtained indicated that
the pyrazole ring can be employed as a directing group in this
type of C−H/C−N bond activation. In addition, no reaction
PnBu3
PCy3
PCy3
P(p-Tol)3
TIPBA
a
Reaction conditions: 1a (0.2 mmol), 2a (1.5 equiv), [RuCl2(p-
cymene)]2 (5 mol %), ligand (10 mol %), and additive (30 mol %) in
b
solvent (1.5 mL) at 100 °C under a N2 atmosphere for 24 h. Isolated
c
yield. No reaction was observed; the starting materials were
recovered.
obtained along with 4-methyl-N-phenylbenzenesulfonamide as
byproduct. The solvent was screened using sodium acetate
(NaOAc) as the additive and PtBu3·HBF4 as the ligand at 100
°C under a nitrogen atmosphere for 24 h. Among the solvents
examined [toluene, 1,2-dichloroethane (DCE), tetrahydrofur-
an (THF), 1,4-dioxane, N,N-dimethylformamide (DMF),
tertiary butanol (tBuOH), and acetone], acetone proved to
be the best solvent (entries 1−7). Usually, an additive which
will react with a precatalyst to produce active species is
necessary in TM-catalyzed C−H bond activation reactions.18
Therefore, the additives were subsequently screened using
acetone as the solvent. The efficiency of salt (NaOAc) and
acids [acetic acid (AcOH), trifluoroacetic acid (TFA), pivalic
acid (PivOH), 1-adamantane carboxylic acid (1-AdCO2H),
benzoic acid (PhCO2H), and 2,4,6-trimethylbenzoic acid
(MesCO2H)] was investigated. A relatively high yield (64%)
was obtained when MesCO2H was utilized as the additive
(entry 13 vs entries 7−12). The ligands were finally screened
using acetone and MesCO2H as the solvent and additive,
respectively. Among the phosphine ligands [tri-tert-butylphos-
phine tetrafluoroborate (PtBu3·HBF4), triphenylphosphine
(PPh3), tri-n-butylphosphine (PnBu3), and tricyclohexyl-
phosphine (PCy3)] examined, the use of PCy3 led to the
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Table 2. Ru-Catalyzed C−H/C−N Activation: Scope of 2-
Table 3. Ru-Catalyzed C−H/C−N Activation: Scope of
a b
,
a
Phenylpyridines
Amides
a
Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv), [RuCl2(p-
cymene)]2 (5 mol %), P(p-Tol)3 (10 mol %), TIPBA (30 mol %), and
K2CO3 (1.1 equiv) in acetone (1.5 mL) at 100 °C under N2
b
c
atmosphere for 24 h. Isolated yield. The reaction was carried out
at 120 °C using PCy3 (10 mol %) as the ligand instead of P(p-Tol)3.
reaction of 1a proceeded smoothly even though the loadings
of precatalyst, ligand, and additive were decreased. This finding
suggests that this protocol opens up an opportunity for the
large-scale acylation of 2-arylpyridines (see the Supporting
Information). The C−H acylation product 3aa was then
transformed to a cyclic pyridinium bromide 4 through
sequential reduction using NaBH4 and cyclization under acidic
conditions (Scheme 2).19 The cyclic pyridinium bromide 4
was quantitatively transformed to an indolizine product 5 when
it was treated with sodium carbonate (Na2CO3) in aqueous
medium.
a
Reaction conditions: 1 (0.2 mmol), 2 (1.5 equiv), [RuCl2(p-
cymene)]2 (5 mol %), P(p-Tol)3 (10 mol %), TIPBA (30 mol %), and
K2CO3 (1.1 equiv) in acetone (1.5 mL) at 100 °C under a N2
atmosphere for 24 h. Isolated yield. Aldol condensation between
product and acetone was occurred.
b
c
or decomposition of starting material was observed when the
starting materials 1u, 1v, and 1w containing oxazoline or imine
directing groups were examined (for details, see SI).
Scheme 2. Transformation of C−H Acylation Product 3aa
to Indolizine 5
The scope of the amides was then investigated using 1a as
the reaction partner. The results are shown in Table 3. The
meta- and para-fluorinated benzamides 2b and 2c smoothly
underwent the target acylation reaction to offer products 3ba
and 3ca in satisfactory yields (52% and 68%, respectively).
However, the para-chlorinated analog 2d gave the desired
product 3da in low yield (40%) owing to the side reaction that
occurred on the C−Cl bond. A low yield (34%) was observed
again when the amide 2e, which bears a methoxycarbonyl
group on the para-position, was examined; the reason is
attributed to the instability of 2e. Consistent with literature
reports,3a,5 an electron-donating group linked to the benzene
ring of amide might reduce the reactivity of amide. The
reactions of amides bearing an electron-donating group at the
ortho-, meta-, or para-position were performed in the presence
of electron-rich phosphine ligand PCy3 at enhanced temper-
ature to obtain satisfactory yields. The acylation products 3fa−
3ka were obtained with 47%−76% yields. The aliphatic amide
2l was also examined, and product 3la was obtained in 82%
yield.
Control experiments were conducted to gain insights into
the underlying mechanism of Ru-catalyzed aromatic C−H and
amide C−N bond activation (Scheme 3). A 11:14 ratio of 3ab
to 3ag was observed in the intermolecular competition
reaction between 1b and 1g, indicating that the electronic
property (electron-donating or electron-withdrawing) of the
substituent linked to the benzene ring did not exert a
remarkable influence on the reactivity of 2-arylpyridines. The
deuterium kinetic isotope effect was investigated by conducting
an intermolecular competition reaction between 1a and 1a-d5.
The 1:1 ratio of 3aa to 3aa-d4 demonstrated that the cleavage
of the aromatic C−H bond in 1a was not the rate-determining
step (see the Supporting Information). This observation
suggests that the cleavage of the amide C−N bond should
be the rate-determining step. The ruthenium carboxylate
complex 6 was considered to be an active catalyst species in the
The substrate 1a was finally scaled-up to 6 mmol to verify
the usefulness of the current Ru-catalyzed C−H/C−N
activation reaction. The ortho-C−H bond benzoylation
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Scheme 3. Control Experiments of Ru-Catalyzed C−H/C−
N Activation
Scheme 4. Proposed Mechanism of Ru-Catalyzed C−H/C−
N Activation
produce the desired ortho-acylation product 3aa and
regenerate the cycloruthenated species 7.
current tandem C−H/C−N activation reaction. Therefore, the
reaction of 1a with 2a was investigated in the presence of
complex 6 as the catalyst to confirm our conjecture. As
expected, the target reaction proceeded smoothly to furnish
the desired acylation product 3aa in high yield (Scheme 3a,
71%). The desired product 3aa was also obtained in 63% yield
by using cycloruthenated complex 7 as the catalyst, indicating
that the complex 7 was another active catalyst species in the
current tandem C−H/C−N activation reaction (Scheme 3b).
The desired product 3aa could not be obtained by direct
treatment of cycloruthenated complex 7 with 2a in the absence
of 1a, whereas the product 3aa was obtained in 18% yield
when 0.2 equiv of 1a was added into the above-mentioned
reaction mixture (Scheme 3c). The acylation products 3aa and
3ab were obtained in 27% and 31% yields, respectively, when
the substrate 1b was added into the above-mentioned reaction
mixture instead of substrate 1a (Scheme 3c). These findings
are consistent with the literature report16a that a bis-
cycloruthenated intermediate generated from complex 7 is
the key intermediate that activates the amide C−N bond.
Based on the previous reports16 and our experimental
outcomes, a plausible mechanism for ruthenium-catalyzed C−
H/C−N activation is shown in Scheme 4. Initially, the Ru(II)
biscarboxylate complex 6, an active catalyst species, is
generated in situ from the reaction of precatalyst [RuCl2(p-
cymene)]2 with 2,4,6-triisopropylbenzoicacid (TIPBA) in the
presence of base K2CO3. Then five-membered cyclometalated
complex 7 is formed through the ortho-ruthenation of 1a with
complex 6. Subsequently, a bis-cycloruthenated intermediate 8
would form through the ortho-ruthenation of another 1a with
complex 7. Oxidative addition of intermediate 8 to the amide
C−N bond takes place to generate the acylruthenium(IV)
intermediate 9, which then undergoes reductive elimination to
In summary, we described a new strategy for amide C−N
bond activation with a Ru catalyst. The Ru-catalyzed tandem
C−H and C−N bond activation reaction proceeded smoothly
at mild conditions to produce monoacylation products in
moderate to good yields. Notable features of our approach
include the following: (a) the use of air stable and inexpensive
Ru(II) catalyst; (b) the reaction shows specific monoacylation
selectivity; (c) no alkylation reaction via the release of carbon
monoxide takes place; (d) broad substrate scope and good
functional group tolerance. Further study on the theoretical
explanation of the reaction mechanism is currently underway
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.1c00464.
Experimental details and compound characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Sheng Zhang − State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian 116023, China;
orcid.org/0000-0002-9671-7668; Email: mingbao@
dlut.edu.cn
Ming Bao − State Key Laboratory of Fine Chemicals, Dalian
University of Technology, Dalian 116023, China;
orcid.org/0000-0002-5179-3499; Email: shengzhang@
dlut.edu.cn
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Authors
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Letter
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Chemoselective Ketone Synthesis via N−C Cleavage in Twisted
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Wenkuan Li − State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian 116023, China
Xiujuan Feng − State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian 116023, China
Xiaoqiang Yu − State Key Laboratory of Fine Chemicals,
Dalian University of Technology, Dalian 116023, China;
orcid.org/0000-0001-9396-3882
Yoshinori Yamamoto − State Key Laboratory of Fine
Chemicals, Dalian University of Technology, Dalian 116023,
China; Research Organization of Science and Technology,
Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00464
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to the National Natural Science
Foundation of China (Nos. 21573032 and 21602026) and the
Fundamental Research Funds for the Central Universities (No.
DUT20LK42) for their financial support. This work was also
supported by LiaoNing Revitalization Talents Program
(XLYC1802030) and the Natural Science Foundation of
Liaoning, China (No. 2019JH3/30100001).
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