[Cp*RhIII]/Ionic Liquid as a Highly Efficient and Recyclable Catalytic Medium for C?H Amidation

Article abstract of DOI:10.1002/cssc.201801287

A [Cp*Rh^III]-catalyzed direct C?H amidation is carried out in ionic liquid. Both C(sp²)?H bonds of (hetero)arenes and alkenes and unactivated C(sp³)?H bonds can be easily amidated with high functional-group tolerance and excellent yields under these conditions. Notably, using [Cp*Rh^III]/[BMIM]BF₄ (BMIM=1-butyl-3-methylimidazolium) as the green and recyclable medium is environmentally benign, in light of characteristics such as the reusability of the expensive rhodium catalyst, avoidance of highly toxic organic solvents, and mild reaction conditions, as well as a short reaction time.

Full text of DOI:10.1002/cssc.201801287

Accepted Article
Title: Cp*Rh(III)/Ionic Liquid as a Highly Efficient and Recyclable
Catalytic Media for C-H Amidation
Authors: Yong Wu, Qiantao Wang, Xinling Yu, Qiang Ma, Ruizhi Lai,
Songyang Lv, Weiyang Dai, Xiaolong Wang, and Chen Zhang
This manuscript has been accepted after peer review and appears as an
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To be cited as: ChemSusChem 10.1002/cssc.201801287
Link to VoR: http://dx.doi.org/10.1002/cssc.201801287
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10.1002/cssc.201801287
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Cp*Rh(III)/Ionic Liquid as a Highly Efficient and Recyclable
Catalytic Media for C-H Amidation
Qiang Ma+, Xinling Yu+, Ruizhi Lai, Songyang Lv, Weiyang Dai, Chen Zhang, Xiaolong Wang, Qiantao
Wang* and Yong Wu*
Abstract: A novel protocol of Cp*Rh(III)-catalyzed direct C-H
amidation in ionic liquid is established. Both C(sp2)-H bonds of
(hetero)-arenes, alkenes and unactivated C(sp3)-H bonds can be
easily amidated with high functional group tolerance and excellent
yields under this condition. Particularly, using Cp*Rh(III)/[BMIM]BF4
as the green and recyclable media is environmentally benign due to
its peculiar characteristics such as (i) reuse of an expensive rhodium
catalytic system, (ii) avoiding the use of highly toxic organic solvents,
(iii) mild reaction conditions as well as short reaction time.
chlorobenzene (PhCl),[11] xylene[5b,12] are the most common
solvents for C-H amination. Therefore, replacement of those
harmful organic solvents with an eco-friendly medium is one of
the major focus of green chemistry. In this regard, polyethylene
glycol and water were recently investigated and successfully
employed as solvents for the transformation.[13] But their
applications are restricted by their low solubility of many
lipophilic organic reagents and catalysts. Ionic liquids (ILs)
generally consisting of an organic cation (such as an
imidazolium or pyridinium core) and a weakly nucleophilic anion,
have drawn the great attention of scientific and industrial
communities due to its outstanding merits of low toxicity,
nonflammability, recyclability, excellent chemical and thermal
stability, negligible vapor pressure as well as good solubility of
organic and inorganic compounds.[14] Since these liquids are
able to dissolve several transition metal complexes, in recent
years, they have often been employed in several catalytic
organic reactions to enhance reaction rates and selectivity. [15]
Nitrogen-containing molecules are important for natural products,
pharmaceuticals and agrochemicals.[1] For this reason, many
research efforts have been directed towards the construction of
carbon-nitrogen bonds.[2] In the past few years, transition-metal-
catalyzed C-H bond functionalization of the unreactive C-H
bonds has been established as a potent tool to generate a wide
range of new carbon-carbon, carbon-heteroatom bonds and
heterocyclic scaffolds by the use of suitable Lewis basic
directing group.[3] Generally, the directing group possesses a
lone pair which coordinates to the transition-metal catalyst to
direct ortho functionalization via a five- or six-membered
metallacycle thus enabling regiospecific introduction of the other
group. Along this line, various coupling partners have been used
as efficient aminating or amidating sources to construct carbon-
nitrogen bonds. And these nitrogen sources could be
summarized into three categories: electrophilic amines,[4] neutral
amines[5] and azides (Scheme 1a).[6] Compared with traditional
coupling reactions, like Ullmann and Buchwald-Hartwig
couplings,[2a-c] the major advantage of C-H amination or
amidation is avoiding the prefunctionalization of the substrates,
which greatly simplifies the synthetic procedures. Dioxazolone
was applied as a new type of amidating reagent firstly by Chang
(Scheme 1b).[7] Carbon dioxide is the only byproduct generated
during the reaction. Consequently, this user-friendly reagent has
come to the fore for the high atomic economy and safety.[8]
Solvent is generally the largest component in most reactions and
plays an important role in organic synthesis. Many low polar but
toxic solvents, for example 1,2-dichloroethane (DCE),[3m,4b,4d,8a-g]
1,2-dichlorobenzene (DCB),[3l,9] tetrahydrofuran (THF),[4c,10]
[*]
Q. Ma,[+] Dr. X. Yu, [+] R. Lai, , Dr. S. Lv, Dr. W. Dai, C. Zhang, X.
Wang, A.P. Dr. Q. Wang, Prof. Dr. Y. Wu
Key Laboratory of Drug-Targeting of Education Ministry and
Department of Medicinal Chemistry, West China School of
Pharmacy, Sichuan University
Chengdu, 610041, P.R. China.
E-mail: wyong@scu.edu.cn; qiantao_wang@hotmail.com
These authors contributed equally to this work.
[+]
Supporting information for this article can be found under:.
DOI: 10.1002/anie.2016XXXXX
Scheme 1. Strategies for direct C–H amidation.
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10.1002/cssc.201801287
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However, as far as we know, it is rarely employed for transition-
metal-catalyzed C–H activation.[16] Our group previously reported
1,2,3-triazole-assisted C−H amidation by cobalt(III) catalysis
(Scheme 1c).[8k] In order to develop more efficient and selective
C−N bond-forming reactions, we herein report a rapid and green
method for the amidation of various C(sp2)−H and C(sp3)−H
bonds by using Cp*Rh(III)/ionic liquid as a highly efficient and
recyclable catalytic media (Scheme 1d).
using [{Cp*RhCl2}2]/AgSbF6 as a catalyst system, coupling
occurred in 1-butyl-3-methylimidazolium tetrafluoroborate
([BMIM]BF4) at room temperature afforded the product 3aa in
85% yield (Table 1, entry 1). To optimize the yield of the
orthoamidated derivative, we screened several parameters, and
the results were shown in Table 1. It was found that transition
metals, such as ruthenium,[6b,6d,13d] palladium[3a,3e,3q,11a] and
cobalt complexes,[3i,8a,8b,8g,8h] which are known to be effective in
direct C-H bond functionalization, were intolerable in this
transformation (entries 4-6). Control experiment also confirmed
that the rhodium-catalyst was essential for this reaction (entry 7).
At the outset of our studies, we explored the feasibility of the
envisioned Rh(III)-catalyzed C-H amidation of 2-phenylpyridine
(1a) with 3-phenyl-1,4,2-dioxazol-5-one (2a). To our surprise,
Table 1. Optimization of the reaction conditions.[a]
Yield
[%][b]
Entry
Catalyst
(5 mol %)
Addictive
(20 mol %)
Solvent
Time
(h)
1
2
3
4
[{Cp*RhCl2}2]
RhCl3·3H2O
Rh2(OAc)4
AgSbF6
AgSbF6
AgSbF6
AgSbF6
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
12
12
12
12
85
-
-
[{Ru(p-
< 5
cymene)Cl2}2]
5
6
Pd(OAc)2
[Cp*Co(CO)I2]
-
AgSbF6
AgSbF6
AgSbF6
-
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]NTf2
[BMIM]PF6
[BMIM]OTf
[BDMIM]BF4
[BPy]BF4
12
12
12
12
12
12
12
12
12
12
12
12
12
5
-
-
7
-
8
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
[{Cp*RhCl2}2]
-
9
AgOAc
AgNTf2
AgOTf
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
73
81
77
84
78
39
81
-
10
11
12
13
14
15
16
17
18
19[c]
20[d]
21[e]
[BTMG]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
[BMIM]BF4
-
84
83
85
85
6
4
1
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), addictive (20 mol %)
and catalyst (5 mol %) in solvent (0.1 M of 1a) were used at 25 °C under air.
[b] Yield of product isolated after column chromatography. [c] 0.05 M of 1a. [d]
0.25 M of 1a. [e] 0.5 M of 1a. Cp* = pentamethylcyclopentadienyl; [BMIM] = 1-
butyl-3-methylimidazolium; [BDMIM] = 1-butyl-2,3-dimethylimidazolium; [BPy]
= 1-butylpyridinium; [BTMG] = 2-butyl-1,1,3,3-tetramethylguanidinium.
Scheme 2. Reaction scope of C(sp2)−H Amidation. Reaction conditions: 1 or 4
(0.2 mmol), 2a (0.24 mmol), [{Cp*RhCl2}2] (5 mol %), and AgSbF6 (20 mol %) in
[BMIM]BF4 (0.4 mL) were used at 25 °C for 1 h under air. Yield is that of
product isolated after column chromatography. [a] Reaction was performed for
5 h. [b] Reaction was performed for 3 h. [c] 2a (0.48 mmol).
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Furthermore, AgSbF6 could promote this reaction and other
silver salts, such as AgOAc, AgNTf2 and AgOTf also displayed
some activity, but proved to be less effective (entries 8-11).
Then we focused our attention on the solvent. [BMIM]BF4,
Transformations of C(sp2)-H bonds are favored by
precoordination of the arene π system, and the resulting aryl-
metal bonds are typically stronger than the corresponding alkyl-
metal bonds. Whereas, metal-catalyzed functionalizations of
unactivated C(sp3)-H bonds are considered to be particularly
challenging for both kinetic and thermodynamic reasons.[17]
Nevertheless, the amidation of 8-methylquinoline derivatives
(6a-f) proceeded smoothly under the standard condition, and the
corresponding amidation products 7aa-fa were isolated in 51-
[BMIM]PF6,
[BMIM]NTf2,
1-butyl-2,3-dimethylimidazolium
tetrafluoroborate ([BDMIM]BF4) could afford the product in good
to excellent yield, but other type of ILs were ineffectual (entries
12-17). [BMIM]BF4 was chosen as the best solvent. Based on
the above results, we then investigated the concentration of the
substrates. It was surprising that the reaction rate was greatly
improved by increasing the concentration of the substrates
(entries 18-21). And the reaction time could be shortened to 1
hour with a 0.5 mol/L concentration of 1a.
With the optimized conditions in hand, we set out to explore the
feasibility and generality of this coupling system (Scheme 2). A
wide range of phenylpyridine derivatives with various electron-
donating (1b, 1c, 1h, 1i) and electron-withdrawing (1d-g, 1j-n)
groups on different positions of the phenyl ring were well
tolerated. It needs to be mentioned that amidation only occurred
at the ortho position relative to the 2-pyridyl moiety in the
presence of other potential directing groups such as ketone and
ester (1m, 1n). Besides pyridine, other N-containing
heterocycles, such as quinoline (1s), pyrazole (1t), oxazole (1u)
and pyrimidine (1v) could also act as viable chelating groups in
this amidation reaction, providing the corresponding products in
80% to 97% yields. For instance, 1-phenyl-1H-pyrazole (1t)
gave the desired product 3ta in 90% yield by prolonging reaction
time to 3 hours. We were also interested in the replacement of
N-heterocycles with other more synthetically useful moieties.
Commonly used amide (1w), N-nitrosoaniline (1x), N-oxide (1y)
and ketoxime (1z) were all found to facilitate ortho-selectivity
efficiently (3wa−za), and only monoamidation product was
observed. To further evaluate the scope of this process,
heteroarenes such as thiophene (4a), indole (4b) and indoline
(4c) were also found to be suitable substrates and afforded the
products in great yields. More importantly, this reaction was not
limited to direct (hetero)arenes functionalizations, alkenes were
identified as amenable substrates as well, delivering the desired
products in high yields (5da-fa).
Scheme 4. Reaction scope of dioxazolones. Reaction conditions: 1a (0.2
mmol), 2 (0.24 mmol), [{Cp*RhCl2}2] (5 mol %), and AgSbF6 (20 mol %) in
[BMIM]BF4 (0.4 mL) were used at 25 °C for 1 h under air. Yield is that of
product isolated after column chromatography. [a] Reaction was performed
for 3 h.
Scheme 5. Reaction scope of enaminones. Reaction conditions: 9 (0.2
mmol), 2a (0.24 mmol), [{Cp*RhCl2}2] (5 mol %), and AgSbF6 (20 mol %) in
[BMIM]BF4 (0.4 mL) were used at 25 °C for 1 h under air. Yield is that of
product isolated after column chromatography.
Scheme 3. Reaction scope of C(sp3)−H Amidation. Reaction conditions:
6 (0.2 mmol), 2a (0.24 mmol), [{Cp*RhCl2}2] (5 mol %), and AgSbF6 (20
mol %) in [BMIM]BF4 (0.4 mL) were used at 25 °C for 2 h under air. Yield
is that of product isolated after column chromatography.
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92% yields by prolonging reaction time to 2 hours (Scheme 3).
Additionally, the scope of dioxazolones was examined under the
established conditions (Scheme 4). Amidating reagents bearing
various electron-donating (2b, 2c, 2e, 2f) and electron-
withdrawing groups (2d, 2g) on the different positions of the
phenyl ring were fully tolerated. Heterocycle-containing
dioxazolone (2h) was also smoothly amidated by this catalytic
system. In addition, dioxazolones having alkyl substituents at the
3-position were highly facile to afford the desired products (3ai,
3aj) in moderate to good yields ranging from 61% to 89%.
successfully employed under the above catalytic system
(Scheme 5). The representative hydrolysis−cyclization of the
amidated product (9aa) with 2.0 N hydrochloric acid solutions
smoothly gave the quinolone derivative 10 in 80% yield (Scheme
6).
To investigate the reusability of the catalyst and solvent, the
recycling of the Cp*Rh(III)/[BMIM]BF4 system was investigated
under the optimized conditions (Figure 1). After the reaction was
complete, diethyl ether was added and shaken. The upper layer
of diethyl ether contains a product mixture directly used for
purification and the lower layer contains [BMIM]BF4 with a
catalytic system. The Cp*Rh(III)/[BMIM]BF4 medium was further
subjected to vacuum to remove the rest of diethyl ether before it
was reused in subsequent reactions. It was observed that this
system was utilized repeatedly five times without much loss in its
activity and the slight decrease in yield might be lost during
workup.
The resulting amidation derivatives are not only common
subunits in many molecules, but also served as important
intermediates of synthesis many heterocycle structures. The
quinolin-4(1H)-one moiety has been shown to exhibit a broad
spectrum of pharmacological and biological activities such as
antibiotic,[18] antidiabetic,[19] antimalarial,[20] anticancer,[21] and
antiviral properties.[22] In 2017, a new two-stage synthetic
strategy to access 4-quinolone derivatives using enaminone as
a weakly coordinating directing group has been developed by Li
and Zhu respectively.[8e,8l] Consequently, we were curious
whether similar directing effects can also be displayed under our
reaction system. Fortunately, a number of enaminones were
To further verify the recovery and practicability of this catalyst
system, we next decided to carry out recycling experiments in
which substrate changed after each catalytic run. Thus, after
setting up
a reaction between 2-phenylpyridine (1a) and
dioxazolone 2a (Table 2, cycle 1), Cp*Rh(III)/[BMIM]BF4 system
were recovered as stated in the previous paragraph. The so-
recycled material was then treated with m-methylphenylpyridine
(1b) and dioxazolone 2a, being the mixture vigorously stirred for
Scheme 6. Synthesis of NH quinolone.
Figure 1. Recyclability of Cp*Rh(III)/[BMIM]BF4 in the C-H amidation between
phenylpyridine 1a and dioxazolone 2a.
Table 2. Recyclability of Cp*Rh(III)/[BMIM]BF4 in the C-H amidation
between dioxazolone 2a and phenylpyridine 1a or m-methylphenylpyridine
1b.[a]
Cycle
Phenylpyridine
Yield [%]
1
2
3
1a
1b
1a
85
94
85
[a] Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), [{Cp*RhCl2}2] (5
mol %), and AgSbF6 (20 mol %) in [BMIM]BF4 (0.4 mL) were used at 25 °C
for 1 h under air. Recycling was performed as stated in the main text.
Scheme 7. Mechanistic findings.
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1 hour, to render amidated product 3ba in excellent yield (cycle
2), without any product 3aa coming from the previous run. After
recycling Cp*Rh(III)/[BMIM]BF4 system from the second cycle, a
third reaction could be run within the same medium employing 2-
phenylpyridine (2a, cycle 3). Gratifyingly, the desired amide 3aa
was produced with comparable selectivity as those of Figure 1,
entry 3, and Table 2, entry 1, which refer to the same product.
And 3ba was not detected as a contaminant.
In summary, we have developed the first general procedure for
direct C-H amidation under ambient reaction conditions using
Cp*Rh(III)/[BMIM]BF4 as
a
highly efficient, green and
sustainable system. Various kinds of DG-containing substrates,
including synthetically useful N-containing hetereocycles, amide,
ketoxime, and N-oxide were selectively amidated with high
regio-stereoselectivity
and
excellent
functional
group
compatibility. Specifically, this strategy allows direct amidation of
both C(sp2)−H and inert C(sp3)−H bonds to yield monoamidation
products without additionally heating and in shorter reaction time
than in organic solvents. A range of quinolone precursors can be
easily synthetized by this newly developed method. Most
importantly, this system is very easy to handle and can be
recycled and reused for at least four runs without showing a
significant loss of activity. We believe that this facile and
environmentally friendly protocol has opened up the applications
of ionic liquids in C–H bond activation.
We next conducted preliminary mechanistic studies to gain
insight into the present reactions (Scheme 7). First, C−H
functionalizations performed in the presence of typical radical
scavengers gave the amidated product 3aa with only a minor
loss in catalytic activity, which indicated that a radical-based
mechanism is unlikely (Scheme 7a). Then, H/D exchange
experiment has been performed. 1H NMR analysis of the
recovered (96% yield) 2-phenylpyridine revealed slight H/D
exchange (17% D) at both ortho positions, and no exchange at
any other position has been observed, which indicated that the
C-H bond cleavage is reversible (Scheme 7b). What’s more, the
parallel reactions (kH/kD = 1.1) and intermolecular competition
(kH/kD = 1.4) using 1a and [D5]-1a consistently gave a relatively
small value, which indicated that cleavage of the C−H bond is
likely not involved with the ratedetermining step (Scheme 7c).
Moreover, intermolecular competition experiments with
differently substituted arenes revealed that an electronrich
substrate showed slightly higher reactivity (Scheme 7d).
Based on the mechanistic studies and the relevant
reports,[7a,8a,8d,8f,8h,23] a plausible mechanistic pathway is depicted
in Scheme 8 with 1a and 2a as model substrates. A cationic
[Cp*Rh(III)] complex is generated in the presence of AgSbF6 in
situ as an active catalyst, which is followed by C-H activation to
give the corresponding five-membered rhodacycle intermediate
A. Coordination of 2a leads to intermediate B, which may
undergo release of CO2 followed by an intermolecular migratory
insertion to furnish six-membered intermediate C. Finally, proto-
demetalation of C delivers the orthoaminated product 3aa and
Experimental Section
General procedure for C−H amidation (3aa as an example)
To a test tube with a magnetic stir bar was added 2-phenyl
pyridine (1a, 31.0 mg, 0.2 mmol, 1.0 equiv), 3-phenyl-1,4,2-
dioxazol-5-one (2a, 39.2 mg, 0.24 mmol, 1.2 equiv),
[{Cp*RhCl2}2] (6.9 mg, 0.01 mmol, 5 mmol %), AgSbF6 (13.7 mg,
0.04 mmol, 20 mmol %) and [BMIM]BF4 (0.4 mL) under
atmospheric conditions for 1 hour. Afterward, the mixture was
extracted with diethyl ether (5 × 1 mL). The organic solvents
were removed under reduced pressure and the residue was
purified by chromatography on silica gel (gradient of Petroleum
ether/EtOAc) to give the desired product 3aa (46.6 mg, 85%) as
a white solid.
Acknowledgements
regenerate
the
rhodiumacycle
species.
We are grateful for support from the National Natural Science
Foundation of China (NSFC) (grant number 81573286,
81773577 & 81602954) and the Fundamental Research Funds
for the Central Universities (grant number YJ201561).
Keywords: C-H amidation • dioxazolones • directing groups •
rhodium • ionic liquids
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10.1002/cssc.201801287
ChemSusChem
COMMUNICATION
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Qiang Ma+, Xinling Yu+, Ruizhi Lai,
Songyang Lv, Weiyang Dai, Chen
Zhang, Xiaolong Wang, Qiantao Wang*
and Yong Wu*
Page No. – Page No.
Cp*Rh(III)/Ionic liquid as a Highly
Efficient and Recyclable Catalytic
Media for C-H Amidation
Cp*Rh(III)/[BMIM]BF4 medium was used as a highly efficient, green and sustainable system for both C(sp2)-H and C(sp3)-H amidation under ambient reaction
conditions. Various kinds of DG-containing substrates were selectively amidated with high regio-stereoselectivity and excellent functional group compatibility.
Most importantly, this system is very easy to handle and can be recycled and reused for at least four runs without showing a significant loss of activity.
This article is protected by copyright. All rights reserved.