Copper(II)-mediated, carbon degradation-based amidation of phenylacetic acids toward N -substituted benzamides

Article abstract of DOI:10.1039/c8ob00064f

The unprecedented synthesis of N-aryl substituted benzamides via the assembly of primary amines and phenylacetic acids has been developed in the presence of copper(ii) acetate. This tandem transformation involving carbon-carbon bond cleavage provides a complementary tool with particular application in the synthesis of secondary benzamides.

Full text of DOI:10.1039/c8ob00064f

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Takeharu Haino et al.
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DOI: 10.1039/C8OB00064F
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ARTICLE
Copper(II)‐mediated, carbon degradation‐based amidation of
phenylacetic acids toward N‐substituted benzamides
Leiling Deng,a Bin Huanga and Yunyun Liua,*
Received 00th January 20xx,
Accepted 00th January 20xx
Abstract. The unprecedented synthesis of N‐aryl substituted benzamides via the assemblies of primary amines and
phenylacetic acids has been developed in the presence of copper (II) acetate. This tandem transformation involving the
carbon‐carbon bond cleavage provides a complementary tool with particular application in the synthesis of secondary
benzamides.
DOI: 10.1039/x0xx00000x
www.rsc.org/
and silver promotion,9b respectively. Notably, by means of
direct transformation on phenylacetic acid, Song and co‐
workers developed a facile carbon‐carbon bond cleavage‐
Introduction
The amide fragment is
a fundamental and featured
based amidation method via the reactions of phenylacetic acid
and ammonium, which features advantages on the easily
available and stable acyl source and the specifically
applicability in the synthesis of primary amides (A, Scheme
1).10a However, a practical method on the synthesis of
corresponding secondary amides by such carbon‐carbon bond
transformation is not yet available. During the process of our
research in developing applicable amidation and their
application in the directed C‐H activation reaction of enhanced
step efficiency,11‐12 we have recently identified that the
phenylacetic acids can react with primary aryl amines to
provide secondary benzamides via carbon‐carbon bond
cleavage in the presence of cooper (II) salt. Herein, we wish to
report this amidation reaction to provide the first example on
the synthesis of secondary amides by the carbon degradation
of phenylacetic acids with primary amines without relying on
substructure in numerous biologically macromolecules and
small organic compounds such as peptides and amino acids. In
addition, amide structure is also found as the key functional
group in many clinical drugs and valuable natural products.1
The synthesis of amide constitutes one central issue
throughout the development of the synthetic organic
chemistry, which correspondingly gives birth to the occurrence
of many different synthetic protocols towards the amides.2
Despite the enriched availability on synthetic methods, the
research work on developing new synthetic accesses to amides
still attracts extensive interest of scientific communities not
only for the requirement of complementary methods featuring
enhanced sustainability and product diversity, but also the
desire in and acquiring and making use of new routes of amide
formation to understand related living processes.3
The C‐C bond cleavage represents one of the most attractive
models of bond transformation in modern organic chemistry,
and the activation of C‐C bond as well as its application in the
designation of fascinating synthetic methods is concurrently
receiving tremendous concerns.4‐5 Among the various known
models of carbon‐carbon bond transformation models, the
cleavage of the carbon‐carbon bonds in carboxylic acids via
decarboxylation and/or other related bond transformation
have been recognized as a reliable tactic enabling the synthesis
of diversified organic products.6‐7 In 2014, Lei and Lan et al
reported the efficient decarboxylative amidation of α‐keto
acids with the mediation of visible light under oxygen
atomsphere.8 Synthesis of similar products has later on been
realized by Xu and co‐workers via singlet oxygen promotion,9a
any additional oxidant besides air (B, Scheme 1).
A) Known: phenylacetic acid amdation for primary amide synthesis
O
Cu2O/O2
H2O
H
H
NH3
Ar
NH2
Ar
COOH
B) Present: phenylacetic acid amdation for secondary amide synthesis
O
H
Ar2
H
Cu(OAc)2/air
Ar2NH2
Ar1
N
Ar1
COOH
p-Xylene
H
Scheme 1 Amidation of phenylacetic acids by carbon degradation
Results and discussion
Originally, when the 2‐aminopyridine 1a was subjected to
react with phenylacetic acid 2a in the presence of CuCl, the N‐
pyridinyl secondary amide 3a was produced by heating in p‐
xylene at 120 C (entry 1, Table 1). Considering the novelty of
this amidation and the importance of the N‐pyridinyl
a. College of Chemistry and Chemical Engineering, Jiangxi Normal University,
Nanchang 330022, P.R. China. Email: chemliuyunyun@jxnu.edu.cn
Electronic Supplementary Information (ESI) available: [General experimental
information, full characterization data, 1H and 13C NMR spectra for all products].
See DOI: 10.1039/x0xx00000x
o
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J. Name., 2013, 00, 1‐3 | 1
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benzamide synthesis,13 we then conducted systematic N‐pyridinyl amides
Journal Name
was found with satisfactoryVtieowleArrtaicnlecOenlitnoe
3
experiment to optimize the reaction parameters. The substituents in both components. FuncDtiOoIn: 1a0l.1g0r3o9u/Cp8sOsBu0c0h06a4Fs
employment of several different copper (II) and copper(I) salts alkyl, alkoxyl, halogen and (hetero)aryl etc were found all with
proved that Cu(OAc)2 possesses the best activity for this compatibility to this amidation process. The yields were fair to
amidation process (entries 2‐6, Table 1). The subsequent excellent and the electronic property of the substituent
experiments at lower copper (II) loading indicated the less displayed no defined effect to the formation of the amides.
Cu(OAc)2 led to the decrease in product yield (entries 7‐8, Notably, to further examine the effect of Cu(II) loading to the
Table 1). Subsequently, the reaction was performed in reaction, some entries in this section were also carried out in
different media, including toluene, DMF, DMSO, dioxane and the presence of 40 mol% Cu(OAc)2, and all these entries gave
ethyl lactate (EL), but no further improved yield was observed very low yield of corresponding products, confirming the fact
(entries 9‐13, Table 1). In addition, the parallel reaction that stoichiometric copper(II) salt was necessary for the
o
conducted at 110 C gave lower yield of 3a, and heightening reaction (3a
,
3c
,
3d
,
3n
,
3p).
the reaction temperature could not enhance the result, either
Table 2 Scope for the synthesis of N‐pyridinyl benzamidesa,b,c
(entries 14‐15, Table 1). A control entry performed under N2
showed the formation of product 3a with trace amount,
suggesting the indispensable role of oxygen (air) in the
reaction (entry 16, Table 1). Further examination on the
reaction using catalytic loading of Cu(OAc)2 under O2 was not
practical, demonstrating the crucial role of the stoichiometric
Cu(II) salt (entry 17, Table 1). In addition, the presence of
TEMPO in the reaction showed no evident inhibition to the
reaction, suggesting against the possible free radical pathway
in this reaction (entry 18, Table 1).
Table 1 Optimization on reaction conditionsa
Entry
1
2
Copper
CuCl
CuBr
CuI
Cu(OAc)2
CuSO4
Solvent
p‐xylene
p‐xylene
p‐xylene
p‐xylene
p‐xylene
p‐xylene
p‐xylene
p‐xylene
toluene
DMF
DMSO
1,4‐dioxane
EL
p‐xylene
p‐xylene
p‐xylene
p‐xylene
p‐xylene
T (oC)
120
120
120
120
120
120
120
120
120
120
120
120
120
110
130
120
120
120
Yield (%)b
72
aGeneral conditions: 1 (0.5 mmol), 2 (0.75 mmol), Cu(OAc)2 (0.5 mmol) in p‐
xylene (2 mL), stirred at 120 oC for 16 h under air atmosphere. The yield on the
parenthesis were acquired in the presence of 40 mol% Cu(OAc)2. bYield of
isolated product based on 1. cThe yields in the parenthesis were acquired in the
presence of 40 mol% Cu(OAc)2.
25
31
78
trace
trace
63
74
68
72
64
trace
trace
61
77
trace
15
3
4c
5
6
CuO
7d
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
8e
On the basis of these results, efforts were then further made
in employing analogous heteroaryl amine, the 2‐
aminoquinoline as the reaction partner to react with different
phenylacetic acids. Delightfully, equally fine substrate
9
10
11
12
13
14
15
16f
17g
18h
tolerance and yields of corresponding products
achieved in this section of experiments. As shown in Table 3,
the N‐quinolinyl benzamides were provided with moderate
5 were
5
to excellent yields under the standard reactions, indicating the
general application scope of the present method toward the
synthesis of N‐electron deficient heteroaryl benzamides. The
reaction using N‐methyl 2‐aminopyridine was found
inapplicable for such reaction as no tertiary amide was given,
which could be attributed to the steric hindrance of the N‐
methyl group to the intramolecular addition step (see Scheme
3). In addition, when subjected with 1a, the aliphatic propionic
acid didn’t take part this degradation amidation, either.
51
aGeneral conditions: 1a (0.5 mmol), 2a (0.75 mmol), copper catalyst (0.5 mmol),
in 2 mL solvent, stirred for 16 h under the open air atmosphere. bYield of isolated
c
product based on 1a. The Cu(OAc)2 in the experiment refers to the commercial
Cu(OAc)2∙H2O reagent. d0.4 mmol Cu(OAc)2 was used; e0.6 mmol Cu(OAc)2 was
f
used. Reaction under N2. gReaction under O2 with 0.1 mmol Cu(OAc)2. hIn the
presence of TEMPO (2 eq).
The good results from N‐heteroaryl amines encouraged us to
further explore the possible application of such transformation
in the synthesis of benzamides with full carbon aryl N‐
To examine the application scope, the reactions employing
different 2‐aminopyridines and phenylacetic acids were first
carried out. As showing in Table 2, the expected synthesis of
substitution by accordingly employing anilines
6 to react with
2 | J. Name., 2012, 00, 1‐3
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Table 3 Scope on the synthesis of N‐quinolinyl benzamidesa,b
underwent transformations to give 3a under the atmosphere
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of both air and N2, indicating that the DsOuIb: s10e.q10u3e9n/Ct8CO‐BC00b0o6n4dF
cleavage might mediated by both air and Cu(II) salt (Eqs 4, 5).
O18
standard condition
N2, H2O18 (2 eq)
COOH
N
N
(1)
H
N
NH2
1a
3a-O18, trace
2a
O18
standard condition
N2
COO18
H
N
N
(2)
(3)
H
N
NH2
O
2a-O18
3a-O18, trace
1a
O
standard condition
N
H
N
N
N
N
H
8
3a, 74 %
40 % under air (4)
12 % under N2 (5)
O
standard condition
3a
N
H
O
9
aGeneration reaction conditions as Table 2. bYield of isolated product based on 4.
Following the information from these experiments, the entry
under N2 and related literature knowledge,10b,14 we proposed
the general mechanism of this C‐C bond cleavage based
amidation reaction. As outlined in Scheme 3, the reaction may
start from the amidation of the phenylacetic acid forming
phenylacetic acids. As expected, the corresponding N‐phenyl
benzamides
groups in both aniline and benzoyl fragments, albeit with much
lower yield than corresponding products and (Scheme 2),
7 could be acquired with different functional
3
5
suggesting that the electron deficient aryl amines were much
favourable in this kind of C‐C bond degradation amidation.
Actually, no similar reaction happened when aliphatic amine
such as i‐propylamine was utilized with 2a, supporting that
electron deficient amines were more proper for the reaction.
The product yields from this section were much lower than the
reactions employing 2‐aminopyridines, probably because the
chelation of 2‐aminopyridines with the Cu(II) salt promoted
this amidation reaction.
phenylacetamide
are known to be capable of getting oxidized by oxygen to
generate carbonyl and provide α‐ketoamide The
8. The benzyl methylene C‐H bonds therein
9.
intramolecular nucleophilic addition of the nitrogen atom to
the newly formed carbonyl enables the formation of
intermediate 11. The bond reorganization initiated by the ring
opening provides N‐formyl intermediate 12, which may be
converted to corresponding carboxyl species 13 via the
oxidation of Cu(OAc)2. The decarboxylation of 13 then yields
the amide products 3.
Scheme 2 Synthesis of benzamides employing phenylacetic acids and anilines
In order to probe the possible pathway of this amidation
reaction, a series of control experiments were then conducted.
Firstly, the optimized model reaction in additional presence of
2 equiv. of O18 labelled water from which the corresponding
Scheme 3 The proposed reaction mechanism
product 3a‐
O18 was observed in HRMS with only trace amount
(Eq. 1), suggesting that the oxygen in the product did come
from moisture. Furthermore, the entry utilizing hydroxyl O18
labeled phenylacetic acid as substrate afforded also trace
amount of 3a‐O18, indicating that the hydroxyl in the
phenylacetic acid was not the source of the carbonyl group in
Conclusions
In conclusion, we have disclosed the carbon degradation‐
based amidation reaction via the assembly of phenylacetic
acids and (hetero)aryl primary amines, which provides a series
of N‐(hetero)aryl benzamides. On the basis of known literature
reporting similar phenylacetic acid amidation for the synthesis
of N‐unsubstituted benzamides, the present work partially fills
in the virgin of the C‐C bond cleavage amidation of
product
3, either (Eq 2). Notably, when the N‐pyridinyl
phenylacetamide was subjected to the standard reaction
condition, the product 3a was isolated with good yield (Eq 3),
supporting that this phenylacetamide was a possible key
intermediate in the reaction. In addition,
α‐ketoamide 9
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4
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To a 25 mL round‐bottom flask equipped with stirring bar and
air condenser was charged with aryl amine or ) (0.5
mmol), phenylacetic acid (0.75 mmol), Cu(OAc)2 (0.5 mmol)
.
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(
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2
and p‐xylene (2 mL). The resulting mixture was stirred at 120
oC for 16 h. Upon completion, the reaction mixture was
allowed to cool down to rt, and H2O (5 mL) was added to the
vessel. The resulting suspension was extracted with ethyl
acetate (3 × 8 mL). The organic phases were combined and
dried over Na2SO4. After filtration, the solvent was removed
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residue was subjected to silica gel column chromatography to
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Conflicts of interest
There are no conflicts to declare.
7
Acknowledgements
This work is financially supported by the National Natural
Science Foundation of China (no. 21562024).
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DOI: 10.1039/C8OB00064F
TOC
The carbon degradation-based amidation of phenylacetic acids with aryl amides has
been realized in the presence of Cu(OAc)2, which provides a practical route in the
synthesis of N-aryl secondary benzamides.