Synthesis of acetamides from aryl amines and acetonitrile by diazotization under metal-free conditions

Article abstract of DOI:10.1055/s-0039-1690237

An efficient and metal-free coupling reaction has been developed that affords acetamides from the corresponding aryl amines and acetonitrile. This method tolerates a wide range of functional groups and is selective toward aryl amines. Preliminary mechanistic studies were conducted.

Full text of DOI:10.1055/s-0039-1690237

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
Y.-F. Zeng et al.
Letter
Synlett
Synthesis of Acetamides from Aryl Amines and Acetonitrile by
Diazotization under Metal-Free Conditions
Yao-Fu Zenga,b
Me
Yi-Na Lia
Na-Na Zhangb
Huan Kangb
Pan Duanb
Fang Xiaoa
HN
X
O
NH2
CH3CN, H2O
R
R
TfOH, t-BuONO, 60 o
C
X
X = C, N
R = OMe, OH, CO2Et, CF3,
NO2, F, Cl, Br, I
Yu Guoa,b
Xianghao Wen*c
without metal catalyst
selective to aromatic amines
22 examples up to 85% yield
a Institute of Pharmacy and Pharmacology, University of South
China, Hengyang, 421001, P. R. of China
zengyf@usc.edu.cn
b School of Pharmaceutical Science, University of South China,
Hengyang, 421001, P. R. of China
c Affiliated Nanhua Hospital, University of South China, Heng-
yang, 421001, P. R. of China
Received: 27.07.2019
O
Accepted after revision: 15.10.2019
Published online: 23.10.2019
DOI: 10.1055/s-0039-1690237; Art ID: st-2019-l0392-l
O
O
HO
H
O
N
N
HN
N
O
NH2
H
O
Abstract An efficient and metal-free coupling reaction has been de-
veloped that affords acetamides from the corresponding aryl amines
and acetonitrile. This method tolerates a wide range of functional
groups and is selective toward aryl amines. Preliminary mechanistic
studies were conducted.
Oseltamivir
Lidocaine
Paracetamol
Figure 1 Examples of drugs bearing an amide groups
Nitriles are recognized as important synthons that can
be converted into various functional groups, such as car-
boxylic acids, amines, amides, or aldehydes.7 An effective
method for the synthesis of amides is the coupling of ni-
triles with amines in the presence of a ruthenium catalyst,
as first developed by Murahashi et al.8 Subsequently, Pt9
and Fe10 were found to be effective catalysts for this cou-
pling reaction. In 2013, Zhou and co-workers reported a
copper-catalyzed version of the coupling reaction that can
be performed in water.11 However, these methods have sev-
eral disadvantages, such as the use of metals and extra li-
gands and the need for high reaction temperatures. A reac-
tion for the synthesis of amides that proceeds under mild
conditions in the absence of a metal catalyst would be pref-
erable.
In 2016, Pahari and co-workers reported a trimethylsilyl
iodide-catalyzed N-acetylation of aromatic amines by ace-
tonitrile under microwave conditions at 110 °C (Scheme
1a).12 Dai and co-workers developed a sulfonated graphene
oxide (SRGO) catalyst for the N-acetylation of amines with
acetonitrile under sonication (Scheme 1b).13 In these two
reported reactions, acetonitrile was considered to act as the
acylating reagent. Here, we report a TfOH-promoted cou-
pling reaction between an aromatic amine and acetonitrile
in the presence of t-BuONO, which proceeds through diazo-
tization and in which acetonitrile acts as the source of an
acetylamino group (Scheme 1c).
Key words aryl amines, amidation, acetonitrile, diazotization, acet-
amides, coupling reaction
The amide bond is one of the most important and abun-
dant structural motifs found in natural products, peptides,
and pharmaceuticals.1 For instance, oseltamivir,2 lidocaine,3
and paracetamol,4 which are widely used as an antiviral
agent, a local anesthetic, and an antipyretic analgesic, re-
spectively, all contain an amide group (Figure 1). In view of
the significant pharmacological value of amides, various
approaches focusing on their synthesis have been devel-
oped.5 Conventional methods for the construction of the
amide bond involve the use of carboxylic acids or their de-
rivatives, such as acid anhydrides, acyl chlorides, or esters.5c
Although these methods are efficient, they have some lim-
itations. For instance, coupling reagents are always needed
to activate carboxylic acids, leading to the production of
stoichiometric amounts of waste products.5d Furthermore,
acetic anhydride and acyl chlorides are hygroscopic and re-
act readily with water to produce acids as byproducts, mak-
ing isolation procedures more cumbersome.6 Therefore, it is
still desirable to develop new approaches for the synthesis
of amides.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y.-F. Zeng et al.
Letter
Synlett
sults are summarized in Table 1. Investigations of various ac-
ids suggested that TfOH gave the best yield (Table 1, entries
1–5). To our surprise, adding H2O (5.0 equiv) to the reaction
mixture was beneficial for the yield (entry 6), but increasing
its amount had the opposite effect (entries 12–15). Screening
of the reaction temperature showed that the product could
be obtained in 71% yield when the reaction was performed at
60 °C (entry 8). Next, the optimal stoichiometry of TfOH and
t-BuONO to p-toluidine was examined, and the highest yield
was obtained when the ratio of both was increased to 1.5:1
(entry 10). Reducing the reaction time to 12 hours afforded
the product in 62% yield (entry 16). Control experiments
demonstrated that the acid and t-BuONO were both essential
for the reaction, as the use of a catalytic amount of TfOH or
the omission of either TfOH or t-BuONO led to dramatic de-
creases in the yield (entries 17–19).
(a) Pahari
NH2
H
CH3CN
N
R
R
R
TMSCl–KI, 110 °C
O
(b) Dai
H
N
NH2
CH3CN, SRGO
R
O
sonication bath, 60 °C
(c) This Work
NH2
H
N
CH3CN, 60 °C
R
R
O
TfOH, t-BuONO
Scheme 1 Various strategies for the synthesis of amides
For our initial investigations, we chose p-toluidine as a
model substrate and acetonitrile as both the reagent and
solvent. A mixture of p-toluidine and t-BuONO in acetonitrile
was stirred under a variety of acidic conditions, and the re-
Having established the optimal reaction conditions, we
next explored the substrate scope of the amine with CH3CN
(Scheme 2). In general, various aryl amines bearing elec-
Table 1 Optimization of the Reaction Conditionsa
H
TfOH (1.5 equiv)
t-BuONO (1.5 equiv)
N
NH2
R
R
H
O
H2O (5.0 equiv)
CH3CN, 60 °C
NH2
acid, t-BuONO
N
1
2
CH3CN, H2O, Temp.
O
H
H
N
H
H
N
1b
2b
N
N
O
O
O
O
Temp (°C) H2O (equiv) Yieldb (%)
t-Bu
H3CO
Entry
Acid (equiv)
2a, 74%
2b, 83%
2c, 74%
2d, 52%a
1
2
TsOH·H2O (1.2)
CH3SO3H (1.2)
TfOH (1.2)
F3CCO2H (1.2)
AcOH (1.2)
TfOH (1.2)
TfOH (1.2)
TfOH (1.2)
TfOH (1.2)
TfOH (1.5)
TfOH (1.5)
TfOH (1.5)
TfOH (1.5)
TfOH (1.5)
TfOH (1.5)
TfOH (1.5)
TfOH (0.2)
–
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
60
70
60
60
60
60
60
60
60
60
60
60
–
–
50
53
55
37
5
H
H
N
H
H
N
N
N
O
O
O
O
HO
F
Cl
Br
3
–
2e, 42%a
2f, 66%a
2g, 53%
2h, 63%
4
–
H
N
H
N
H
H
N
N
5
–
O
O
O
O
EtO2C
F3C
6
5
60
63
71
51
83
69
55
37
21
48
62
39
24
trace
I
2l, 59%
2i, 60%
2j, 67%
2k, 38%
7
5
H
N
H
N
H
H
N
8
5
N
9
5
O
O
O
O
10c
11c
12c
13c
14c,d
15c,e
16f
17
18
19g
5
F
Cl
Br
OH
2m, 45%
2n, 40%
2o, 39%
2p, 56%
2
H
H
N
N
H
N
H
N
10
20
–
Cl
O
O
O
O
CF3
2q, 61%
NO2
2r, 37%a
2s, 69%
2t, 65%
–
H
H
N
Br
N
5
O
N
O
5
2u, 85%
2v, 68%
5
unsuccessful substrates
H
H
N
TfOH (1.5)
5
H
N
N
a Reaction conditions: 1b (0.5 mmol), t-BuONO (1.2 equiv), acid, MeCN
(3.0 mL), H2O, air atmosphere, 24 h.
b Isolated yield.
O
O
O
O2N
OCH3
c t-BuONO (1.5 equiv).
2w, trace
2x, trace
2y, 0%
d CH3CN (1.5 mL) + H2O (1.5 mL).
e CH3CN (2.0 mL) + H2O (1.0 mL).
f 12 h.
Scheme 2 Scope of amines. Reagents and conditions: 1 (1.0 mmol, 1.0
equiv), t-BuONO (1.5 mmol, 1.5 equiv), TfOH (1.5 mmol, 1.5 equiv),
H2O (5.0 equiv), CH3CN (5.0 mL), 60 °C, 24 h, in air. a At 120 °C.
g Without t-BuONO.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

C
Y.-F. Zeng et al.
Letter
Synlett
tron-withdrawing or electron-donating functional groups
were successfully converted into the corresponding amides
in yields ranging from 37 to 85%. Various substituents such
as fluoro (2f and 2m), chloro (2g, 2n, and 2t), bromo (2h,
2o, and 2u), iodo (2i), ethoxycarbonyl (2j), hydroxy (2e and
2p), or trifluoromethyl (2k and 2q) were well tolerated un-
der the standard conditions. However, a higher temperature
was needed for substrates bearing 4-methoxy (2d), 4-hy-
droxy (2e), 4-fluoro (2f), or 3-nitro groups (2r). Notably, 4-
aminopyridine (2v) was also a suitable substrate for the re-
action, affording the corresponding product in 68% yield.
Unfortunately, this method was not compatible with alkyl
amines (2y), and only trace amounts of products were de-
tected for substrates containing 4-nitro (2w) or 3-methoxy
(2x) groups.
H
N2OTf
TfOH (1.5 equiv)
N
(1)
H2O (5.0 equiv)
CH3CN, 60 °C
O
3
2b
with t-BuONO, 58%
without t-BuONO, 55%
H
N
H
N
NH2
TfOH (1.5 equiv)
or
(2)
t-BuONO (1.5 equiv)
H2O18 (5.0 equiv)
CH3CN, 60 °C
18O
16O
1b
2b-18
O
2b-16
O
2b-18O / 2b-16O > 95:5
H
NH2
TfOH (1.5 equiv), t-BuONO (1.5 equiv)
N
(3)
(4)
H2O (5.0 equiv), CH3CN, 60 °C
O
TEMPO/BHT (1.5 equiv)
2b
1b
To demonstrate the scalability of this method, we car-
ried out a gram-scale reaction under the standard condi-
tions. To our delight, this reaction of 1b with t-BuONO in
the presence of TfOH in CH3CN at 60 °C provided amide 2b
in 70% yield (Scheme 3).
with TEMPO, 26%
with BHT, 75%
H
N
N2OTf
TfOH (1.5 equiv), H2O (5.0 equiv)
CH3CN, 60 °C, TEMPO (1.5 equiv)
O
3
2b
with t-BuONO, 62%
without t-BuONO, 83%
H
NH2
TfOH (1.5 equiv)
N
Scheme 4 Preliminary mechanistic studies
t-BuONO (1.5 equiv)
H2O (5.0 equiv)
CH3CN, 60 °C
O
2b, 1.04 g, 70%
1b, 1.07 g
CH3
NH2
t-BuONO
N2
Scheme 3 Gram-scale synthesis of amide 2b
OTf
N
C
N
CF3SO3H
–N2
CCH3
1a
H2O
To elucidate the mechanism of this reaction, some pre-
liminary experiments were performed (Scheme 4). When
the arenediazonium triflate 3 was synthesized and exposed
to the standard reaction conditions, the amide product 2b
was obtained in 58% yield. Furthermore, this reaction also
proceeded in the absence of t-BuONO, suggesting that the
arenediazonium salt might be an intermediate in the origi-
nal transformation (Scheme 4, eq. 1). An isotope-labeling
experiment indicated that the oxygen atom of the amide
might originate from H2O (Scheme 4, eq. 2). We then con-
ducted two radical-trapping experiments. When 2,2,6,6-te-
tramethylpiperidine 1-oxyl (TEMPO) was added, product
2b was obtained in 26% yield, whereas butylated hydroxy-
toluene (BHT) had little effect on the transformation
(Scheme 4, eq. 3). In addition, the arenediazonium triflate 3
could be successfully converted into the product 2b in the
presence of TEMPO (Scheme 4, eq. 4).
I
II
CH3
CH3
C
H
N
C
H
CH3
N
O
H
N
OH
O
III
2a
OTf
Scheme 5 Proposed mechanism
In conclusion, we have developed a TfOH-promoted
method for the preparation of acetamides from aryl amines
and CH3CN under metal-free conditions.16 This method tol-
erates a wide range of functional groups and is selective to-
ward aryl amines. Preliminary mechanistic studies indicated
that an arenediazonium salt is generated in the reaction
process.
Based on the above mechanistic studies and previous
reports,14 a proposed mechanism is outlined in Scheme 5.
Aniline is initially converted into the arenediazonium tri-
flate I in the presence of t-BuONO and TfOH.15 Subsequent-
ly, this arenediazonium triflate is trapped by CH3CN with
release of nitrogen gas and the generation of cation II. Final-
ly, cation II is attacked by H2O to deliver the enol III, which
isomerizes into product 2a. However, an alternative radical
mechanism for the reaction cannot be excluded.14b
Funding Information
This research was supported by the "Double First-Class" Discipline
Construction Foundation of the University of South China
(2017SYL06), the Undergraduate Training Programs for Innovation
and Entrepreneurship in Hunan Province (S201910555144), and the
Foundation of Hunan Educational Committee (18C0476, 18C0467).()
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

D
Y.-F. Zeng et al.
Letter
Synlett
Supporting Information
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7846.
(9) Cobley, C. J.; van den Heuvel, M.; Abbadi, A.; de Vries, J. G. Tetra-
hedron Lett. 2000, 41, 2467.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690237.
S
u
p
p
orit
n
gInformati
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gInformati
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2016, 57, 1158.
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(16) Acetamides 2a–v; General Procedure
To a stirred solution of the appropriate arylamine (1.0 mmol) in
CH3CN (5.0 mL) were added t-BuONO (1.5 mmol, 1.5 equiv),
TfOH (1.5 mmol, 1.5 equiv), and H2O (5.0 mmol, 5.0 equiv). The
mixture was stirred under air at 60 °C for 24 h until the reaction
was complete. The resulting mixture was purified by flash chro-
matography (silica gel, PE–EtOAc).
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N-(4-Tolyl)acetamide (2b)
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White solid; yield: 83%; 123.8 mg; mp 150–151 °C. 1H NMR
(500 MHz, CDCl3):  = 7.44 (br s, 1 H), 7.37 (d, J = 8.1 Hz, 2 H),
7.10 (d, J = 8.1 Hz, 2 H), 2.30 (s, 3 H), 2.14 (s, 3 H). 13C NMR (126
MHz, CDCl3):  = 168.5, 135.4, 134.1, 129.6, 120.2, 24.6, 21.0.
MS (ESI): m/z = 150 [M + H]+
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D