Direct synthesis of N-arylamides via the coupling of aryl diazonium tetrafluoroborates and nitriles under transition-metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2018.07.014

The direct synthesis of N-arylamides via the coupling of aryl diazonium tetrafluoroborates and nitriles under transition-metal-free conditions has been developed. The reported protocol is practical and represents an efficient method to produce functionalized amides in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2018.07.014

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
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Direct synthesis of N-arylamides via the coupling of aryl diazonium
tetrafluoroborates and nitriles under transition-metal-free conditions
⇑
Biquan Xiong , Gang Wang, Tao Xiong, Liming Wan, Congshan Zhou, Yu Liu, Panliang Zhang,
⇑
Changan Yang, Kewen Tang
Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang 414006, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct synthesis of N-arylamides via the coupling of aryl diazonium tetrafluoroborates and nitriles
under transition-metal-free conditions has been developed. The reported protocol is practical and repre-
sents an efficient method to produce functionalized amides in moderate to good yields.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 25 May 2018
Revised 29 June 2018
Accepted 3 July 2018
Available online xxxx
Keywords:
N-arylamide
Aryl diazonium tetrafluoroborates
Nitriles
Transition-metal-free
Introduction
N-nucleophiles [7c]. In 2013, Xiang, Wang and co-workers
disclosed the copper-catalyzed amidation of aryl halides with
Amides are privileged scaffolds in various bioactive natural
products and synthetic therapeutic agents [1–2]. Additionally, they
are key intermediates for the preparation of bioactive materials
and asymmetric catalysts, and are also used as indicators in chem-
ical laboratories and as biological stains [3]. For example, amide
derivatives have been used for the treatment of a variety of
conditions, ranging from sleep disturbances, to antibacterial and
herbicidal treatments (Scheme 1) [4].
The direct amidation of primary anilines with aromatic car-
boxylic acids has provided a straightforward and reliable approach
for preparing amides (Scheme 2). However, this method has the
disadvantages of low selectivity and product yields [5], and gener-
ally requires high temperatures and strong Brønsted acids which
limits functional group compatibility. The orthodox nucleophilic
substitution of acyl chlorides with primary amines is also exten-
sively used for the preparation of amides [6].
nitriles; this represents the first direct amidation of nitriles [7d].
Chen and co-workers found that in the presence of copper,
diphenyliodonium triflates could react efficiently with nitriles to
afford the corresponding amides [7e]. Meanwhile, the direct
amidation of anilines and their derivatives with alcohols using a
water-soluble Au/DNA catalyst has been systematically
investigated by Wang and co-workers [7f]. Later, Zhu and co-
workers developed the synthesis of arylcarboxyamides from aryl
diazonium salts and isocyanides [7g]. In 2015, the copper
catalyzed para-selective CAH amidation of simple arenes with
nitriles was reported by Xiang and co-workers [7i]. The
condensation reaction of amines with carboxylic acids employing
a modified light-fluorous Mukaiyama reagent has been reported
by Matsugi and co-workers [7o]. However, most of these
reactions require transition-metal catalysts, and a systematic
study of the direct amidation of nitriles with aryl diazonium salts
has not been reported. Encouraged by these works [7–9], herein,
we report a base-promoted direct amidation of nitriles with aryl
diazonium tetrafluoroborates under mild conditions. The proposed
method is novel and practical for realizing the direct synthesis of
N-arylamides. A plausible reaction mechanism is also proposed.
In 2008, Bolm and co-workers reported an iron-based catalyst
system for the efficient N-arylation of primary amides with aryl
iodides [7a,7h]. In addition, the xenon difluoride-mediated, ipso-
amidation of boronic acids was achieved by Olah and co-workers
[7b]. Later, Singh and co-workers disclosed the nickel-mediated
Chan-Lam type cross-coupling of arylboronic acids with various
Results and discussion
⇑
Corresponding authors.
E-mail addresses: xiongbiquan@126.com (B. Xiong), tangkewen@sina.com
The model reaction of phenyl diazonium tetrafluoroborate (1a)
with acetonitrile (2a) at 80 °C with the assistance of H2O in the
(K. Tang).
https://doi.org/10.1016/j.tetlet.2018.07.014
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
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B. Xiong et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Table 1
Optimization of the reaction conditions.a
Entry
Base
Solvent
Temp.
Yield 3a (%)b
1
2
3
4
5
6
7
8
Na2CO3
K2CO3
K3PO4
NaHCO3
Cs2CO3
Et3N
DBU
DIPEA
–
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOAc
DCE
THF
1,4-Dioxane
Toluene
DMF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
25 °C
40 °C
100 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
80 °C
78%
86%
93%
75%
49%
61%
<10%
<10%
Trace
88%c
65%c
52%c
28%c
70%c
19%c
17%
Scheme 1. Structures of selected important bioactive amides.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
39%
84%
22%d
81%e
93%f
71%g
92%h
86%i
21%j
a
Reagents and conditions phenyl diazonium tetrafluoroborate (0.5 mmol),
CH3CN (1.0 mL), base (0.6 mmol), H2O (1.5 mmol), solvent (1.0 mL), N2 atmosphere,
temp., 12 h.
b
Yield determined by GC analysis, using dodecane as the internal standard.
CH3CN (0.6 mmol).
K3PO4 (0.1 mmol).
K3PO4 (0.5 mmol).
K3PO4 (1.0 mmol).
H2O (0.5 mmol).
H2O (2.5 mmol).
Air atmosphere.
Scheme 2. Selected strategies for the synthesis of amides.
c
d
e
f
g
presence of Na2CO3 under a N2 atmosphere gave N-phenylac-
etamide 3a in 78% yield (Table 1, entry 1). In the reaction, acetoni-
trile was used in excess and also served as the solvent. Other
inorganic and organic bases such as K2CO3, K3PO4, NaHCO3, Cs2CO3,
Et3N, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) and DIPEA (N,N-
diisopropyl ethyl amine) were also tested. The results show that
the use of K3PO4 is better than the other bases tested, and 3a
was obtained in 93% yield using a phenyl diazonium tetrafluorob-
orate/K3PO4 molar ratio of 1:1.2 (Table 1, entries 2–8). When the
reaction was carried out without the addition of a base, the desired
amidation product was only formed in trace amounts. In order to
expand the generality of the reaction, other solvents such as EtOAc,
DCE (1,2-dichloroethane), THF, 1,4-dioxane, toluene, and DMF
were examined, where acetonitrile (1.2 equiv.) was used as the
substrate. Performing the reaction in EtOAc gave 3a in 88% yield.
The increase of reaction temperature within the 25–80 °C range
is beneficial, but a further increase from 80 to 100 °C resulted in
a reduced yield (Table 1, entries 3, 16–18). In addition, we studied
the effect for the amount of K3PO4 and found that when the
amount was reduced from 1.2 to 1.0 equivalents, the yield
decreased from 93% to 81%, and a further reduction to 0.2 equiva-
lents caused a further decline to 22%. Increasing the amount of
K3PO4 from 1.2 to 2.0 equivalents, did not significantly increase
the yield (Table 1, entries 1, 19–21). When the reaction was per-
formed under an air atmosphere, the expected amidation product
3a was only obtained in 86% yield. This phenomenon may be
ascribed to the oxygen in the air, which interrupted the radical
reaction. A further experiment was performed under an O2 atmo-
sphere, and 3a was only formed in 21% yield (Table 1, entry 25).
With the optimized reaction conditions in hand, we investigated
the effect of H2O amount, and found that a phenyl diazonium
h
i
j
O2 atmosphere.
tetrafluoroborate/H2O molar ratio of 1:3 was optimal (Table 1,
entries 22–23).
The base-promoted direct amidation reaction turned out to be
general for organic nitriles and their derivatives. As shown in
Table 2, different types of aliphatic nitriles such as acetonitrile,
acetonitrile d3, 2,2,2-trichloro acetonitrile, 2-bromo acetonitrile,
pentanenitrile and cyclopropanecarbo-nitrile reacted efficiently
with phenyl diazonium tetrafluoroborate (1a) under the optimized
reaction conditions to afford the corresponding amidation
products in good to excellent yields (Table 2, 3a-f). In addition,
the reaction of 1a with benzonitrile afforded the desired N-phenyl-
benzamide (3g) in 78% yield. It was observed that cinnamonitrile
(1h) and 2-phenylacetonitrile (1i) also exhibited high reactivity,
affording the corresponding amidation products in moderate to
good yields, (Table 2, 3h-i). Furthermore, different substituted aro-
matic nitriles such as 3-methoxybenzonitrile, 3-methylbenzoni-
trile and 2-methylbenzonitrile were tested, and amides 3j-l were
formed in 56–73% yield. However, 4-chloro-N-phenylbenzamide
(3m) and 3,4-difluoro-N-phenylbenzamide (3n) were only synthe-
sized in trace amounts. In most cases, substituents on the aryl ring
or the nitrile group (Table 2, 3a-b, 3e-l) did not alter the yields of
the amidation products significantly. However, if the aromatic
nitriles were substituted with an electron-withdrawing group,
the corresponding amidation products were only formed in trace
amounts. This phenomenon may be ascribed to the deactivating
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B. Xiong et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 2
reaction of acetonitrile with 4-phenoxy-phenyl diazonium
tetrafluoroborate. When 4-N,N-dimethyl-phenyl diazonium
tetrafluoroborate (1k) and 2-thiazole diazonium tetrafluoroborate
(1l) were used, N-(4-(dimethylamino) phenyl)acetamide (4j) and
N-(thiazol-2-yl)acetamide (4k) were obtained in 76% and 60%
yield, respectively. However, when 4-nitro-phenyl diazonium
tetrafluoroborate (1m) was used, the expected amidation product
(4l) was not formed, which may be due to the strong electron-
withdrawing effect of this substrate.
Scope of the nitriles.a
Control experiments were conducted to gain insight into the
reaction mechanism (Scheme 3). When the radical scavenger
2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) was added, only
trace amounts of 3a were observed. These results indicated that
a phenyl radical may be generated during the reaction. In addition,
3a was not detected from the reaction of acetonitrile with phenyl
diazonium tetrafluoroborates in the absence of H2O. When D2O
and H128O were reacted under the optimal conditions, the corre-
sponding deuterated N-phenylacetamide (3a’) and 18O isotope
labelled N-phenylacetamide (3a’’) were formed in 92% and 89%
yield, respectively. The exact molecular weights and structures of
3a’ and 3a’’ were confirmed by GC-MS and NMR analysis (ESI).
Based on these results, we deduced that the hydrogen atom and
oxygen atom which located in the amide bond were derived from
H2O.
A plausible mechanism for the presented amidation reaction is
proposed in Scheme 4[7g,7n]. Aryl radical (B) is first generated
from aryl diazonium tetrafluoroborate (A) in the presence of a
base. Then the aryl radical B attacks nitrile (C) to form adduct D.
Simultaneously, a single electron transfer (SET) process occurrs in
D to generate the corresponding N-alkylidyne aryl aminium E. In
the presence of H2O, the amidation process is completed via
nucleophilic addition to afford amide (F).
a
Reagents and conditions: phenyl diazonium tetrafluoroborate (0.5 mmol),
nitrile (for liquid nitrile: 1.0 mL, for solid nitrile: 0.6 mmol), K3PO4 (0.6 mmol),
EtOAc (1.0 mL, for solid nitriles), H2O (1.5 mmol), N2, 80 °C, 12 h; bIsolated yield.
cGC yield. dN.D. = Not detected.
effects of the electron-withdrawing group on the aryl ring of these
substrates (Table 2, 3m-n).
As depicted in Table 3, we further investigated the reaction of
different types of aryl diazonium tetrafluoroborates (1b-m) with
acetonitrile under the optimized conditions. 4-Bromo-phenyl
diazonium tetrafluoroborate, 4-chloro-phenyl diazonium tetraflu-
oroborate, 3-chloro-phenyl diazonium tetrafluoroborate and 3,4-
dichloro-phenyl diazonium tetrafluoroborate reacted efficiently
with acetonitrile (2a) to give the corresponding amidation prod-
ucts 4a-d in 68–82% yield. Aryl electron-donating groups substi-
tuted diazonium tetrafluoroborates such as 4-methyl-phenyl
diazonium tetrafluoroborate, 4-methoxy-phenyl diazonium
tetrafluoroborate and 2-methyl-4-methoxy-phenyl diazonium
tetrafluoroborate were also good substrates, and amides 4e-g were
formed in 71–91% yield. Interestingly, when 3-ethynyl-phenyl
diazonium tetrafluoroborate (1i) was used, the expected coupling
product of 4h was obtained in 77% yield. In addition, N-(4-phe-
noxyphenyl)acetamide was also formed in 85% yield via the
Table 3
Scope of the aryl diazonium tetrafluoroborates.a
Scheme 3. Mechanistic investigations.
a
Reagents and conditions: aryl diazonium tetrafluoroborate (0.5 mmol), CH3CN
(1.0 mL), K3PO4 (0.6 mmol), H2O (1.5 mmol), N2, 80 °C, 12 h; bIsolated yield.
cN.D. = Not detected.
Scheme 4. Proposed mechanism.
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B. Xiong et al. / Tetrahedron Letters xxx (2018) xxx–xxx
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In summary, we have developed an efficient direct synthesis of
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and nitriles under transition-metal-free conditions. The approach
avoids the use of strong acids and air-sensitive reagents, and the
reaction can be performed under mild conditions, making the
experimental procedure simple.
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