Ligand-free copper-catalyzed direct amidation of diaryliodonium salts using nitriles as amidation reagents

Article abstract of DOI:10.1016/j.tetlet.2021.153048

An efficient and practical methodology for the synthesis of N-arylamides has been developed via copper-catalyzed amidation of diaryliodonium salts with nitriles. Various substituted aryl nitriles and aliphatic nitriles could be applied in the reaction, providing a series of N-arylated amides in moderate to good yields. This procedure provides an alternative route for the synthesis of various N-arylamides. A proposed mechanism based on control experiments is also presented.

Full text of DOI:10.1016/j.tetlet.2021.153048

Tetrahedron Letters 71 (2021) 153048
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Ligand-free copper-catalyzed direct amidation of diaryliodonium salts
using nitriles as amidation reagents
a
a
a,
a
a
Hui-cheng Cheng a, , Lichao Zhou , Xuming Zhou , Jiao-li Ma , Penghu Guo , Yang Zhang ,
⇑
⇑
Hong-bing Ji a,b
a College of Chemistry, Guangdong University of Petrochemical Technology, Maoming 525000, PR China
b Fine Chemical Industry Research Institute, School of Chemistry, Sun Yat-sen University, Guangzhou 510275, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and practical methodology for the synthesis of N-arylamides has been developed via copper-
catalyzed amidation of diaryliodonium salts with nitriles. Various substituted aryl nitriles and aliphatic
nitriles could be applied in the reaction, providing a series of N-arylated amides in moderate to good
yields. This procedure provides an alternative route for the synthesis of various N-arylamides. A proposed
mechanism based on control experiments is also presented.
Received 15 February 2021
Revised 24 March 2021
Accepted 28 March 2021
Available online 31 March 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Copper catalyst
Diaryliodonium salts
N-Arylamides
Synthesis
Amidation
Introduction
Amides are important structure scaffolds existing in natural
products, biological compounds, pharmaceuticals and synthetic
materials [1,2]. In particular, N-arylamides are prevalent in various
structurally diverse pharmaceutical products. Therefore, the syn-
thesis of them has aroused great interest from organic chemists
and extensive efforts have been devoted to the synthesis of N-ary-
lamides. As an early methodology for the construction of CAN
bond, Jourdan reaction, Ullmann reaction and Goldberg reaction
often suffered from drastic reaction condition, limited substrate
tolerance and poor yield [3].
In recent decades, the ligand assisted modifications in these
reactions and Buchwald-Hartwig cross-coupling reaction greatly
simplified the synthesis of N-arylamides and enabled to develop
useful synthetic strategies under the mild conditions [Scheme 1,
Eq. (1)] [4–6]. Although Buchwald-Hartwig reaction has significant
advantages in terms of yield and catalytic performance, palladium
catalyst with high price, strong toxicity and dependence on highly
toxic phosphorus ligands are severely restricted. The groups of
Chan, Evans, and Lam independently reported Cu-mediated oxida-
tive amination of arylboronic acids with amines and other nucle-
Scheme 1. Selected strategies for the synthesis of N-arylamides.
ophiles for the formation of C,aryl)-N bonds [7]. Recently, Cu-
mediated oxidative amination of arylboronic acids as aryl donors
with amides or nitriles was has been widely illustrated by the
groups of Yu, Li, Lan and Xiang, independently [Scheme 1, Eq.
(2)] [8]. Over the last few years, the direct CAH amination of arenes
has been proven to be a powerful tool for the CAN bond formation
[Scheme 1, Eq. (3)] [9,10]. Transition metal-catalyzed
chelate-assisted CAH amidation provided a valuable alternative
for synthesis of N-amides [9]. Meanwhile, Xiang groups reported
the metal-free oxidative amidation of simple arenes using ArI
(OAc)2 as oxidant [10].
⇑
Corresponding authors.
E-mail addresses: cheng@gdupt.edu.cn (H.-c. Cheng), xiaojiaoli.good@163.com
(J.-l. Ma).
https://doi.org/10.1016/j.tetlet.2021.153048
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

Hui-cheng Cheng, L. Zhou, X. Zhou et al.
Tetrahedron Letters 71 (2021) 153048
Diaryliodonium salts have recently gained considerable atten-
tion and are employed widely as mild, selective, and environmen-
tally benign electrophilic arylating agents in organic synthesis [11].
As reported previously, diaryliodonium salts have been known to
transform into aryl radicals via decomposition in acetonitrile, and
acetanilide as one of the products has been was observed [12].
Chen group presented an efficient and regioselective synthesis of
multiply substituted quinolines from diaryliodoniums, alkynes,
and nitriles [13]. Cu-catalyzed ring opening/amination of cyclic
diaryliodonum salts by Wen, Gu and Jiang was reported [14].
Table 1
Optimization of the reaction conditions.a
entry
X
Catalyst
solvent
Yieldb2a, %)
1
2
3
4
5
6
7
8
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
BF4
PF6
Br
CuCl
CuCl
CuCl
CuCl
CuCl
CuI
Cu(OTf)2
CuSO4Á5H2O
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
–
PhCH3
THF
DMSO
1,4-dioxane
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
9
<5
<5
<5
67
50
88
44
88
trace
trace
trace
0
9
10
11
12
13
14c
OTf
OTf
–
DCE
0
a
b
c
Reaction conditions: 1a (0.30 mmol), CH3CN (3.0 equiv), H2O (1.0 mmol), Cu salts (10 mol %), solvent (2.0 mL), 80 °C, air, 20 h. Isolated yield. 100 °C, N2, 20 h.
Table 2
Substrate scope of nitriles.a
a
b
Reaction conditions: 1a (0.30 mmol), RCN (3.0 equiv), H2O (1.0 mmol), Cu(OAc)2 (10 mol %), DCE (2.0 mL), air, 20 h. Isolated yield.
CuCl (10 mol %).
2

Hui-cheng Cheng, L. Zhou, X. Zhou et al.
Tetrahedron Letters 71 (2021) 153048
Table 3
Results and discussion
Substrate scope of diaryliodonium salts.a
We started our investigations with di(p-toly)liodonium trifluo-
romethanesulfonate 1a with acetonitrile as the model substrate,
and the effect of solvents and metal catalysts were systematically
examined (Table 1). A screening of solvents revealed that DCE
proved to be the most effective solvent in the reaction, affording
the N-(p-tolyl)acetamide 2a in 67% yield. Other solvents such as
CH3CN, DMSO, 1, 4-dioxane and THF gave a lower yield (Table 1,
entries 1–5). In a set of copper sources screened, Cu(OTf)2 and Cu
(OAc)2 exhibited superior results compared to CuSO4Á5H2O, CuI
and CuCl (entries 5–9). (p-toly)liodonium salts (1a-1d), bearing dif-
ferent counter anions were studied (Table 1, entries 9–12). Among
all the tested reagents, (p-toly)liodonium triflate furnished the
desired product 2a in 88% yield (Table 1, entry 9), whereas tetraflu-
oroborate, Hexafluorophosphate and bromide gave lower yields
(Table 1, entries 10–12). Finally, control experiments confirmed
that without the Cu source no product was observed (entry 13).
We performed this reaction only at elevated temperature as an
additional control (entry 14). After 20 h at 100 °C, no product 2a
was observed (determined by GC–MS and 1H NMR spectroscopy).
After establishing these conditions, we selected di(p-tolyl)iodo-
nium trifluoromethanesulfonate 1a as the partner to react with dif-
ferent nitriles to evaluate the substrate scope of the nitriles. The
results in Table 2 show that both aryl nitriles and aliphatic nitriles
could undergo this transformation to generate the desired prod-
ucts in moderate to excellent yields (57–88%). The desired prod-
ucts in excellent yields were obtained when aliphatic nitriles
were selected as the substrates (2a-2e, Table 2). Pleasingly, substi-
tuted benzonitriles bearing electron-donating and electron-with-
drawing groups smoothly underwent this reaction generating the
desired products in good yield (2f-2l, Table 2). Halogenated ben-
zonitriles with F or Cl smoothly led to the corresponding amides
with the halogen substituents intact (2h-2j, Table 2). The hetero-
cyclic aromatic nitriles also successfully underwent the reaction
to afford the desired products in 81% yield (2l, Table 2). However,
the reaction did not occur for five-membered cyclic diaryliodo-
nium salts to provide the desired product (2m, Table 2). Impor-
tantly, six-membered cyclic diaryliodonium salts with a range of
nitriles (e.g. acetonitrile, benzonitrile and phenylacetonitrile)
delivered the desired amide products in good yields (2n-2p,
Table 2).
a
Reaction conditions: 1a (0.30 mmol), RCN (3.0 equiv), H2O (1.0 mmol), Cu(OAc)2
b
(10 mol %), DCE (2.0 mL), air, 20 h. Isolated yield. CuCl (10 mol %).
Moreover, nitriles are utilized widely in organic reactions as versa-
tile synthons in organic synthesis [15,16]. Nitriles as nitrogen
nucleophilic reagents instead of amides can make the synthesis
of N-arylamides more accessible [15]. It is reported
recently that copper-catalyzed acylation of cyclic diaryliodoniums
with nitrile species has been developed for the preparation of
iodo-functionalized diarylmethane amides [16a]. Recently, we
developed a general and practical method for the synthesis of
tertiary amides via the copper-catalyzed aerobic oxidative
amidation of tertiary amines [17]. Base on such results, we report
a direct copper-catalyzed amidation of diaryliodonium salts with
nitriles for the synthesis of N-arylamides [Scheme 1, Eq. (4)].
Subsequently, the reactivity of different diaryliodonium salts
with isobutyronitrile was investigated in this amidation. As shown
in Table 3, the diaryliodonium salts containing substituents in the
para, meta and ortho positions of the aryl moiety were efficiently
coupled with the isobutyronitrile, producing the corresponding
desired products with 31–88% yields (Table 3, 3a–3n). However,
the steric hindrance of diaryliodonium salts affected this reaction
significantly (Table 3, 3a–3e vs 3f-3g). When unsymmetrical iodo-
nium salts were used in the amidation, the desired products were
obtained in moderate yield (Table 3, 3i–3n). When a methyl was
Scheme 2. Control experiments.
3

Hui-cheng Cheng, L. Zhou, X. Zhou et al.
Tetrahedron Letters 71 (2021) 153048
Acknowledgments
We are gratefulfor financial support from the National Natural
Science Foundation of China (21938001, 21961160741,
22078072), Guangdong Basic and Applied Basic Research
Foundation (2019A1515110346), Science and Technology Plan of
Maoming (2019401, 2020581), Scientific Research Fundation of
Guangdong University of Petrochemical Technology (517152,
2019rc053).
Appendix A. Supplementary data
Supplementary material that may be helpful in the review pro-
cess should be prepared and provided as a separate electronic file.
That file can then be transformed into PDF format and submitted
along with the manuscript and graphic files to the appropriate edi-
torial office. Supplementary data to this article can be found online
at https://doi.org/10.1016/j.tetlet.2021.153048.
Scheme 3. Proposed mechanism.
present in the ortho position of the phenyl group of the iodonium
salt, the desired product was isolated in 31% yield (Table 3, 3f).
In contrast, the methyl group was para or meta to the iodonium
salt, and the desired compounds were obtained in 88% and 67%
yields, respectively (Table 3, 3a and 3l). To our delight, the desired
amide product was obtained by reacting the six-membered cyclic
diaryliodonium salts with cyclopropylcarbonitrile as the cyclic
counterpart in 52% yield (Table 3, 3h).
Some control experiments were performed to probe the mech-
anism of the amidation reaction. The observations were listed in
Scheme 2.The diaryliodonium salt 1a was employed to react with
acetonitrile to get the corresponding product 2a in a yield of 88%
[Eq. (1), Scheme 2]. It was found that no product 2a was detected
when using acetamide to react with di(p-tolyl)iodonium trifluo-
romethanesulfonate 1a instead of acetonitrile under the standard
condition [Eq. (2), Scheme 2]. These results indicate that the possi-
bility of amide from the hydrolysis of nitriles being involved in the
reaction might be ruled out.
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