Rh(III)-Catalyzed C-H Amidation of Arenes with N-Methoxyamide as an Amidating Reagent

Article abstract of DOI:10.1021/acs.orglett.9b02625

The Rh(III)-catalyzed amidation of C(sp²)-H bonds has been reported by employing the N-methoxyamide as a novel amino source. An excellent level of functional group tolerance can be achieved when N-methoxyamide derivatives are used as the amidating reagents. Importantly, several known bioactive compounds such as Aminalon, Pregabalin, Gabapentin, and Probenecid can be transformed to effective amidating reagents, as a way to facilitate the development of new bioactive molecules.

Full text of DOI:10.1021/acs.orglett.9b02625

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rh(III)-Catalyzed C−H Amidation of Arenes with N‑Methoxyamide as
an Amidating Reagent
Guodong Ju,† Guobao Li,† Guanwen Qian,† Jingyu Zhang,*,‡ and Yingsheng Zhao*,†
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, Suzhou 215123, People’s Republic of China
‡College of Energy, Soochow Institute for Energy and Materials Innovations, Soochow University, Suzhou 215006, People’s
Republic of China
S
* Supporting Information
ABSTRACT: The Rh(III)-catalyzed amidation of C(sp2)−H
bonds has been reported by employing the N-methoxyamide
as a novel amino source. An excellent level of functional group
tolerance can be achieved when N-methoxyamide derivatives
are used as the amidating reagents. Importantly, several known
bioactive compounds such as Aminalon, Pregabalin, Gaba-
pentin, and Probenecid can be transformed to effective amidating reagents, as a way to facilitate the development of new
bioactive molecules.
he carbon−nitrogen bond is one of the fundamental
Tchemical bonds, which is a ubiquitous component of
various natural products, pharmaceutical drugs, and materials.1
Thus, the routes to form C−N bonds have been well-explored
in the past decades. Among these well-established methods,
the C−H amidation reaction has provided a direct and efficient
approach to form C−N bonds by avoiding the use of
prefunctionalized substrates.2 The pioneering work reported
by Breslow et al.3 used an iron catalyst and imino-iodane as the
amidating reagent in order to directly achieve the C−H
amidation of cyclohexane. Since then, various catalyst systems4
and new amidating reagents, such dioxazolones,5 chloramines,6
and organic azides,7 have been extensively explored, leading to
great improvements in reaction conditions and the scope of
substrates (Figure 1).
Recently, the researchers in the Glorius group were the first
to report the rhodium-catalyzed amidation of arenes using
electron-deficient aroyloxycarbamates, in order to provide
Figure 1. Novel application for C−N bond formation.
valuable N-Boc-protected arylamines.8 Later, the Chang group
demonstrated that N-substituted hydroxylamines, such as
ing arylamines in good to excellent yields. This new class of
amidating reagents are stable and can be easily synthesized
from carboxylic acids.
aroyloxycarbamates or acyloxycarbamates, can be highly
effective amidating reagents, with rhodium or cobalt as the
catalysts.9 Recently, the Glorius group reported a novel
approach to realize the C−H amidation reaction via an
intramolecular amide transfer process by rhodium catalyst
(Figure 1a).10 Although these examples of amidating reagents
have been presented to perform the C−H amidation reactions,
the development of new and easily accessible amidating
reagents which would be favor for the rapid construction of
significant compounds are still attractive. Herein, we report
that the readily available N-methoxyamides (Figure 1b) can be
used as highly effective amidating reagents in rhodium-
catalyzed C−H amidation reactions. Various types of N-
methoxyamides were well-tolerated, leading to the correspond-
With these conditions in mind, we first assessed whether N-
methoxyamide could be used as an amidating reagent with a
rhodium catalyst, which is a highly active catalyst in C−H
amidating reactions.11 Initially, the 2-phenylpyridine (1a) was
treated with N-methoxybenzamide (2) as a novel amidating
reagent in the presence of [Cp*Rh(III)Cl2]2 (2.5 mol %) in
1,2-dichloroethane at 140 °C for 18 h under nitrogen.
Amidated product 3a was obtained in 8% yield (Table 1,
Received: July 26, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 1. Scope of Aryl-Substituted N-Heterocyclesa
temperature, T
(°C)
yield
(%)
entry
additive
solvent
DCE
DCE
DCE
1
2
3
4
5
6
7
8
9
none
140
140
140
140
140
140
100
140
140
140
140
8
49
10
45
60
91
53
55
43
AgOTf, 1 equiv
AgOAc, 1 equiv
Cu(OTf)2, 1 equiv DCE
Cu(OAc)2, 1 equiv DCE
AgSbF6, 0.1 equiv
AgSbF6, 0.1 equiv
AgSbF6, 0.1 equiv
AgSbF6, 0.1 equiv
AgSbF6, 0.1 equiv
AgSbF6, 0.1 equiv
DCE
DCE
toluene
t-amyl−OH
H2O
10
11
trace
none
DCE
a
1a (0.20 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6
(10 mol %) in solvent (1.5 mL) for 18 h under nitrogen in a sealed
b
c
tube. No [Cp*RhCl2]2. Yields were based on gas chromatography
(GC) analysis, using tridecane as an internal standard.
entry 1). Encouraged by this result, several other additives,
such as AgOTf, AgOAc, Cu(OTf)2, Cu(OAc)2, AgSbF6, were
further explored (Table 1, entries 2−6). Table 1 shows that the
amidated product 3a can be achieved in 91% yield, when 0.1
equiv of AgSbF6 was used as the additive (Table 1, entry 6).
This result may indicate that the reaction can proceed without
an external oxidant. By varying the temperature, it was shown
that the yield of 3a dramatically decreased when the reaction
was performed at 100 °C (Table 1, entry 7). Although the
clear reason is unknown, it might be that the C−O bond
cleavage requires a high reaction temperature. Several other
solvents, such as toluene, t-amyl−OH, and water, were tried to
replace 1,2-dichloroethane. However, none of these solvents
produced the amidated product 3a in good yields, along with
1a being recovery (Table 1, entries 8−10). Control experi-
ments indicate that the rhodium catalyst is essential for this
transformation, while a nitrogen atmosphere guarantees a good
yield for C−H amidation (Table 1, entry 11).
a
1a (0.20 mmol), 2a (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6
(10 mol %) in solvent (1.5 mL) for 18 h under nitrogen in a sealed
tube. One mmol-scale synthesis. Isolated yields.
b
Scheme 2. Scope of Aryl-Substituted N-Heterocyclesa
With optimized reaction conditions in hand, we first
explored the scope of arenes that could be coupled with N-
methoxybenzamide (2a) as listed in Scheme 1. We found that
various functional groups substituted on the phenyl ring, such
as methyl (Me), OMe, F, Cl, CF3, and CO2Me, were well-
tolerated (3b−3g), leading to the corresponding products in
good to excellent yields. The methyl- or fluoro-substituted
pyridines gave good yields in this amidation reaction (3i, 3j).
Phenylisoquinoline is a good substrate for C−H amidation,
leading to the product 3l in 56% yield. The amidation of arenes
containing other heterocyclic compounds as directing groups
were also examined. 2-phenylpyrazole, PPD (Scintillator), and
2,5-diphenyloxazole were readily amidated to provide the
corresponding products (3n−3q). As expected, oxazoline was
a good directing group, yielding the corresponding product 3v
in 70% yield. We further explored whether oxime can be
applied as an effective directing group for these new amidating
reagents. Several substituted phenyl ketoxime and O-methyl-
(E)-benzaldoxime ethers all led to the corresponding products
in good to excellent yields (see Scheme 2, products 4a−4h).
We next surveyed the scope and limitations of the N-
methoxyamide as presented in Scheme 3. First, N-methox-
ybenzamide substituted with various functional groups were
subjected to the standard reaction conditions. A wide variety of
functional groups, including OMe, t-Bu, F, Cl, Br, I, CF3, and
a
1a (0.20 mmol), 2a (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6
(10 mol %) in solvent (1.5 mL) for 18 h under nitrogen in a sealed
tube. Isolated yields.
NO2 substituted in the ortho, meta, or para positions on the
phenyl ring, were all well-tolerated, yielding the corresponding
products in moderate to excellent yields (5a−5m). Reactions
with 2,6-difluoro-substituted N-methoxybenzamide and N-
B
DOI: 10.1021/acs.orglett.9b02625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 3. Scope of Novel Nitrogen Source
Scheme 4. Scope of Aminating Reagent
a
1a (0.20 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6
(10 mol %) in solvent (1.5 mL) for 18 h under nitrogen in a sealed
tube. R2 = Bn. Isolated yields.
b
a
1a (0.20 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (2.5 mol %), AgSbF6
(10 mol %) in solvent (1.5 mL) for 18 h under nitrogen in a sealed
b
tube. R = Me. R2 = Bn. Isolated yields.
methoxyfuramamide had good yields. N-methoxynaphthalene-
2-carboxamide was also a good amidating reagent. When the
N-methoxyalkylamides were used (5q−5y), each of these
amidating reagents can be easily introduced to arenes.
We next explored the challenging aminating reagents based
on cinnamic acid derivatives, and the corresponding aminated
products were all obtained in good yields (Scheme 4, products
6a and 6b). The aminating reagents from sorbic acid and
undecylenic acid were well-tolerated, leading to the corre-
sponding products in good yields (6c and 6d, respectively).
Amino acids are a class of highly important compounds, which
still have been less explored in previous intramolecular
amidation reactions, which, when introduced to the system,
yielded 2-phenypyridine in good to excellent yields (6e−6h).
Several drugs, such as Aminalon,12 Pregabalin,13 Gabapentin,14
and Probenecid,15 were all easily transformed to the
corresponding aminating reagents, which were then success-
fully coupled with 2-phenylpyridine under the standard
reaction conditions via intermolecular C−H amidation (6i−
6l). The key intermediate of Vismodegib16 (6m) and
Fluxapyroxad17 (6n) were also easily introduced to 2-
phenylpyridine in good yields using this new method, which
can facilitate the development of new pharmaceutical drugs.
Several experiments were performed to elucidate the
reaction pathway. When a new aminating reagent 7 was
prepared and used instead of 2 under the standard reaction
conditions (Figure 2a), the aminated product 3a was obtained
at 83% yield, along with 4-biphenylmethanol 8 at 79% yield.
This result strongly supported that when N-methoxyamide was
used as the aminating reagent, the only side product is
Figure 2. Preliminary mechanistic study.
methanol. The complex 9 was synthesized in good yields by
following the reported procedure by Li.18 A good yield of 3a
was achieved when complex 9 was treated with the aminating
reagent, implying its involvement in the catalytic cycle (Figure
2b). When an equivalent amount of potassium acetate was
added to the reaction, only trace amounts of 3a were obtained
while recovering the starting material, indicating that the
hexafluoroantimonic acid plays an important role during the
catalytic cycle (Figure 2c). Based on these results, a plausible
reaction pathway was proposed (see the Supporting
Information for details).
C
DOI: 10.1021/acs.orglett.9b02625
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Catalyzed Direct Amination of Azoles with Chloroamines at Room
Temperature. J. Am. Chem. Soc. 2010, 132, 6900−6901.
(7) (a) Shin, K.; Kim, H.; Chang, S. Transition-Metal-Catalyzed C-
N Bond Forming Reactions Using Organic Azides as the Nitrogen
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In conclusion, we have developed a rhodium-catalyzed
C(sp2)−H amidation reaction with N-methoxyamides as novel
amidating reagents. An excellent level of functional group
tolerance can be achieved with N-methoxyamide derivatives as
the amidating reagents. Importantly, several known bioactive
compounds such as Aminalon, Pregabalin, Gabapentin, and
Probenecid can be transformed to amidating reagents that can
be reacted with arenes, as a way to facilitate the development
of new bioactive molecules.
(8) Grohmann, C.; Wang, H.; Glorius, F. Rh[III]-Catalyzed C-H
Amidation Using Aroyloxycarbamates To Give N-Boc Protected
Arylamines. Org. Lett. 2013, 15, 3014−3017.
ASSOCIATED CONTENT
* Supporting Information
■
(9) (a) Patel, P.; Chang, S. N-Substituted Hydroxylamines as
Synthetically Versatile Amino Sources in the Iridium-Catalyzed Mild
C−H Amidation Reaction. Org. Lett. 2014, 16, 3328−3331. (b) Patel,
P.; Chang, S. Cobalt(III)-Catalyzed C−H Amidation of Arenes using
Acetoxycarbamates as Convenient Amino Sources under Mild
Conditions. ACS Catal. 2015, 5, 853−858.
(10) Wang, X.-M.; Gensch, T.; Lerchen, A.; Daniliuc, C. G.; Glorius,
F. Cp*Rh(III)/Bicyclic Olefin Cocatalyzed C−H Bond Amidation by
Intramolecular Amide Transfer. J. Am. Chem. Soc. 2017, 139, 6506−
6512.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02625.
Experimental procedures, new compounds character-
ization data, including the NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(11) Liang, Y.-F.; Zhang, X.-H.; MacMillan, D. W. C. Decarbox-
ylative sp3 C−N coupling via dual copper and photoredox catalysis.
Nature 2018, 559, 83−88.
*E-mail: jyzhang@suda.edu.cn (J. Zhang)
*E-mail: yszhao@suda.edu.cn (Y. Zhao).
ORCID
(12) ffrench-Constant, R. H.; Rocheleau, T. A.; Steichen, J. C.;
Chalmers, A. E. A point mutation in a Drosophila GABA receptor
confers insecticide resistance. Nature 1993, 363, 449−451.
(13) Schifano, F. Misuse and Abuse of Pregabalin and Gabapentin:
Cause for Concern? CNS Drugs 2014, 28, 491−496.
(14) Attal, N.; Cruccu, G.; Baron, R.; Haanpaa, M.; Hansson, P.;
Jensen, T. S.; Nurmikko, T. EFNS guidelines on the pharmacological
treatment of neuropathic pain: 2010 revision. Eur. J. Neurology. 2010,
17, 1113−1123.
Yingsheng Zhao: 0000-0002-6142-7839
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(15) Butler, D. Wartime tactic doubles power of scarce bird-flu drug.
Nature 2005, 438, 6−6.
(16) Lacroix, M. Targeted Therapies in Cancer; Nova Sciences
Publishers: Hauppauge, NY, 2014.
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2013, 97, 118−122.
(18) Yu, S.-J.; Wang, F.; Wan, B.-S.; Yu, X.-Z.; Li, X.-W.
Rhodium(III)-Catalyzed C−C Coupling between Arenes and
Aziridines by C-H Activation. Angew. Chem., Int. Ed. 2013, 52,
2577−2580.
This work was supported by Natural Science Foundation of
China (Nos. 21772139 and 21572149), Jiangsu Province
Natural Science Found for Distinguished Young Scholars (No.
BK20180041), Project of Scientific and Technologic Infra-
structure of Suzhou (No. SZS201708), and the PAPD Project
are also gratefully acknowledged.
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