A novel and unusual method for C[sbnd]N bond formation between benzene ring and various amines

Article abstract of DOI:10.1016/j.tetlet.2021.153355

A new approach to form C[sbnd]N bond without metal catalysis was developed. 4-acetylbenzoyl isocyanate reacted with various amines through a mild method to form C[sbnd]N bond. This reaction was amenable to scale-up and it afforded the corresponding products with good to excellent yields and tolerates a wide range of functional groups.

Full text of DOI:10.1016/j.tetlet.2021.153355

Tetrahedron Letters xxx (xxxx) xxx
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A novel and unusual method for CAN bond formation between benzene
ring and various amines
⇑
⇑
Peng Wang, Chen Wang, Zhenzhen Zhu, Sicong Xu, Yunlei Hou , Yanfang Zhao
School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new approach to form CAN bond without metal catalysis was developed. 4-acetylbenzoyl isocyanate
reacted with various amines through a mild method to form CAN bond. This reaction was amenable to
scale-up and it afforded the corresponding products with good to excellent yields and tolerates a wide
range of functional groups.
Received 10 June 2021
Revised 2 August 2021
Accepted 17 August 2021
Available online xxxx
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
CAN bond
4-Acetylbenzoyl isocyanate
Various amines
Mild method
Introduction
pling catalyzed by organic photocatalysts. (Scheme 1, Method E)
[13]. Manwika reported that a high-temperature and high-pres-
CAN bond formation is a fundamental reaction in organic
chemistry [1,2]. The reaction is highly important in the synthetic
methodologies and in the preparation of pharmaceutical com-
pounds [3]. Because of its broad applications in various fields,
numerous methods have been documented in the literature for
the formation of this important chemical bond [4]. Migita and
co-workers firstly reported that N, N-diethylaniline was synthe-
sized by using organotin reagent and bromobenzene as the reac-
tion substrate, PdCl2(o-tolyl3P)2 as the catalyst in toluene
(Scheme 1, Method A) [5]. Buchwald and co-workers reported that
using amines instead of highly toxic organotin reagents can also
realize the coupling of CAN bonds [6,7], which was refered to as
the first-generation Buchwald-Hartwig amination reaction.
(Scheme 1, Method B) [8]. Hua-Jian Xu and co-workers reported
that CuCl/ligand-free catalyzed N-arylation of aryl halides with
N-heterocyclic compounds and alkyl amines in water. (Scheme 1,
Method C) [9–11]. Yuqin Xu and co-workers reported that various
N-aryl phosphinamides and phosphonamides were successfully
prepared through the Chan-Evans-Lam reaction. (Scheme 1,
Method D) [12]. Sukanya and co-workers reported that a general
and practical method for direct CAH amination of 2H-indazole
with a series of amines (including aliphatic primary amines, sec-
ondary amines, azoles and sulfonimides) through oxidative cou-
sure continuous-flow protocol to carry out nucleophilic aromatic
substitution (SNAr) of heterocycles with nitrogen nucleophiles.
(Scheme 1, Method F) [14]. However, most of these reported meth-
ods used functionalized starting materials [15], expensive metal
catalysts [16], and strict conditions [17].
Therefore, construction of CAN bond under mild reaction condi-
tions are more attractive in modern synthetic chemistry [18]. Ini-
tially, we attempted synthesis of compounds containing a formyl
urea structure (I). However, the structure of the final compound
was not obtained, but rather to give a CAN coupling product
(3a). This discovery aroused our great interest. In this study, we
reported a convenient method of forming CAN bond by mild
method with 4-acetylbenzoyl isocyanate as material, and it dis-
played wide applicability and good yield.
Results and discussion
In the initial attempt, 4-acetylbenzoyl isocyanate (1a) and
cyclopentanamine (2a) were chosen as model substrates to explore
the optimization of aliphatic amine reaction conditions. Second,
we selected MeCN as the solvent, screening of the reaction temper-
ature from 25 °C to 80 °C. The results indicated that raising the
temperature to 70 °C increased the yield of 3a from 26% to 85%
(Table 1, entry 4). However, raising the temperature from 70 °C
and 80 °C displyed no further effects on the yield (Table 1, entry
5). Third, the reaction solvents were screened. The results revealed
that the yield could not be improved (Table 1, entries 6–11). To our
⇑
Corresponding authors.
E-mail addresses: houyunlei901202@163.com (Y. Hou), yanfangzhao@126.com
(Y. Zhao).
https://doi.org/10.1016/j.tetlet.2021.153355
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Wang, C. Wang, Z. Zhu et al., A novel and unusual method for CAN bond formation between benzene ring and various amines,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153355

P. Wang, C. Wang, Z. Zhu et al.
Tetrahedron Letters xxx (xxxx) xxx
Scheme 1. Synthesis of CAN coupling products.
surprise, when we reduce the reaction time to 1 h, the desired pro-
duct (3a) was obtained in 86% yield (Table 1, entry 12). Conse-
quently, the standard reaction conditions used for further
investigations were 1a (1.0 equiv.) and 2a (1.2 equiv.) in MeCN
at 70 °C for 1 h (Table 1, entry 12).
determine the generality of this method (Table 2). A series
of aliphatic amines were explored and the desired CAN
coupling products were obtained with 74–92% yields. The
results showed that the types of aliphatic amines had little
effect on the yields. These results clearly indicated that the
CAN bond formation could better endure the wide variation
in aliphatic amine.
With the optimized reaction conditions for CAN bond
formation identified, the substrate scope was investigated to
2

P. Wang, C. Wang, Z. Zhu et al.
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Table 1
Optimization of aliphatic amine reaction conditions.
b
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
ClCH2CH2Cl
DCM
1,4-dioxane
THF
DMSO
r.t.
40
60
70
2
2
2
2
2
2
2
2
2
2
2
1
4
26
43
67
85
76
45
18
68
62
46
Trace
86
86
80
reflux
reflux
70
reflux
70
reflux
70
70
9
10
11
12
14
CH3OH
CH3CN
CH3CN
a
Reagents and conditions: 1a (1.0 mmol), 2a (1.2 mmol), solvent (5 mL) was added to the reaction system.
Isolated yield.
b
Table 2
Substrate scope for the CAN bond formation between 1a and aliphatic amine.
b
Entry
NHR1R2
Product
Yield (%)
1
2
3
4
5
6
7
cyclopentanamine
cyclopropanamine
methanamine
pyrrolidine
piperidine
3a
3b
3c
3d
3e
3f
92
87
74
84
87
89
91
4-methylpiperidine
1-methylpiperazine
3g
a
Reagents and conditions:1 (1.0 mmol), 2 (1.2 mmol), CH3CN, 70 °C, 1 h.
Isolated yield.
b
To further expand the scope of the substrates, we took aniline as
yields, which indicated that the reaction might be able to tolerate
large groups. However, the reaction of nitro and chlorine substi-
tuted substrates 3o, 3p and 3q showed an obvious decrease in
yield, which indicated that this reaction is affected by electronic
factors and electron-withdrawing groups are unfavorable.
Finally, we explored the substrate scope of 4-acetylbenzoyl iso-
cyanate and its derivatives (Table 5). Under the optimized reaction
conditions, all substrates with acyl groups on the benzene ring
were converted into the desired CAN coupling products (3v-x) in
64–89% yield. However, the substrates without acyl substitution
couldn’t react with piperidine to obtain the CAN coupling products
(3s-u), which indicated that the presence of acetyl groups were
necessary for this reaction.
an example to optimize a series of reaction conditions for aromatic
amines. First, we selected CH3CN as solvent to react at different
temperatures. However, the yield decreased significantly. As the
influence of solvent was crucial for the reaction, different solvents
were then screened. It was found that when 1,2-dichloroethane
was used as solvent, the yield was increased significantly. Then
the reaction temperature was screened from 25 °C to 60 °C. The
results indicated that reducing the temperature to 25 °C increased
the yield of compound 3 h to 94% (Table 3, entry 8). Thus, the
optimal reaction conditions were 1a (1 equiv.), 2h (1.2 equiv.) in
1,2-dichloroethane at 25 °C for 2 h (Table 3, entry 8).
Under the optimized reaction conditions, we investigated the
range of substrates to verify the generality of the method (Table 4).
A series of substituted anilines with ortho-or para-substituents
were explored and the desired CAN coupling products (3h-p) were
obtained in 48–94% yield. Compounds 3r was also obtained in good
In order to explore the reaction mechanism, various control
experiments were conducted. 4-Acetylbenzoyl isocyanate (1a)
and piperidine (2e) were converted into the CAN coupling product
(3e) in 87% yield under the optimised reaction conditions. When
3

P. Wang, C. Wang, Z. Zhu et al.
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Table 3
Optimization of aromatic amine reaction conditions.
b
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
CH3CN
CH3CN
CH3CN
CH3CN
DCM
DCM
DCM
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
r.t.
40
60
80
r.t.
40
reflux
r.t.
40
2
2
2
2
2
2
2
2
2
2
1
2
2
2
2
2
2
2
23
26
22
24
33
28
24
94
88
87
93
34
29
23
27
45
37
44
9
10
11
12
13
14
15
16
17
18
60
r.t.
r.t.
40
60
80
r.t.
40
reflux
THF
THF
a
Reagents and conditions: 1a (1.0 mmol), 2 h (1.2 mmol), solvent (5 mL) was added to the reaction system.
Isolated yield.
b
Table 4
Substrate scope for the CAN bond formation between 1a and aromatic amine.
b
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
-H
-H
–CH3
-H
-H
-H
-H
-H
-Cl
-H
-H
–CH3
–CH3
–CH2CH3
–CH(CH3)2
–OCH3
-OCF3
-Cl
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
94
92
89
92
86
90
88
54
48
n.d.
85
9
10
11
-H
–NO2
-N(CH2CH2)2O
-H
a
Reagents and conditions:1 (1.2 mmol), 2 (1.2 mmol), 1,2-dichloroethane, 25 °C, 1 h.
Isolated yield.
b
the reaction was conducted in the presence of 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO) or butylated hydroxytoluene (BHT) as
radical scavengers, compound 3e was obtained in 85% and 86%
yield Scheme 2, respectively, which indicated that the reaction
did not proceed via a radical mechanism.
Based on our experimental results and previous investigations,
a plausible mechanism was proposed (Scheme 3) [19,20]. First,
intermediate A was formed by the reaction between benzoyl
isocyanate (1) and amine (2) under acidic condition. Then
intermediate B and C were formed via the tautomerism between
the benzene ring and the acyl group on intermediate A. Second,
the nitrogen atom on the amine attacked the carbocation on the
1-position of the benzene ring to obtain the intermediate D. Third,
intermediate E was formed by breaking the CAN bond. Finally,
intermediate E removed one molecule of formyl isocyanate to
obtain compound 3.
4

P. Wang, C. Wang, Z. Zhu et al.
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Table 5
Substrate scope for the CAN bond formation between 1 and 2e.
b
Entry
R
Product
Yield (%)
1
2
3
4
5
6
-H
p-NO2
p- OCH3
o- COCH3
m- COCH3
p- COCH2CH3
3 s
3 t
3u
3v
3w
3x
n.d.
n.d.
n.d.
89
86
64
a
Reagents and conditions:1 (1.0 mmol), 2e (1.2 mmol), CH3CN, 70 °C, 1 h.
Isolated yield.
b
Scheme 2. Control experiments.
Scheme 3. Proposed mechanism for the formation of 3.
5

P. Wang, C. Wang, Z. Zhu et al.
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Conclusion
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In summary, we have developed an effective CAN bond forma-
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any catalyst. This novel reaction works well with a wide range of
substrates and mild reaction conditions.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgment
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Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153355.
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