Copper(I)-catalysed aerobic oxidative selective cleavage of C[sbnd]C bond with DMAP: Facile access to N-substituted benzamides

Article abstract of DOI:10.1016/j.tetlet.2021.153199

A base/DMAP system for efficient oxidative cleavage of C(CO)–C(alkyl) bond to generate N-substituted benzamides has been developed in the presence of copper(I) chloride. The usage of inexpensive copper catalyst, broad substrate scope, mild conditions make

Full text of DOI:10.1016/j.tetlet.2021.153199

Tetrahedron Letters 75 (2021) 153199
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Copper(I)-catalysed aerobic oxidative selective cleavage of CAC bond
with DMAP: Facile access to N-substituted benzamides
a,
a
Haojie Ma a,b,y, Guoqiang Lu b,c,y, Bo Han a, Guosheng Huang b, , Yuqi Zhang , Ji-Jiang Wang
⇑
⇑
a Key Laboratory of New Energy & New Functional Materials, Shaanxi Key Laboratory of Chemical Reaction Engineering, College of Chemistry and Chemical Engineering,
Yan’an University, Yan’an, Shaanxi, 716000, PR China
b State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, PR China
c Southern Marine Science and Engineering Guangdong Laboratory, Zhanjiang, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A base/DMAP system for efficient oxidative cleavage of C(CO)–C(alkyl) bond to generate N-substituted
benzamides has been developed in the presence of copper(I) chloride. The usage of inexpensive copper
catalyst, broad substrate scope, mild conditions make this protocol very practical. More importantly, this
reaction provides an alternative approach for the construction of useful N-substituted benzamides.
Ó 2021 Elsevier Ltd. All rights reserved.
Received 30 March 2021
Revised 18 May 2021
Accepted 20 May 2021
Available online 24 May 2021
Keywords:
C(CO)
C(alkyl) bond cleavage3
Copper
N-substituted benzamides
Aryl ketones
2-Aminopyridine
The increasing significance of amide in valuable natural prod-
ucts and small organic compounds has prompted chemists to
develop novel methods for their efficient synthesis during the past
decades [1]. Typically, pyridyl benzamides play an important role
in many biological activities, such as luciferase inhibitors, antiulcer
agents, antifungal agents, glucokinase activators, etc [2]. Tradi-
tional methods of amide synthesis relies on preactivation of car-
boxylic acid [3] either by using acetyl chloride or coupling
reagents. However, these methods have their own drawbacks
which include requirements of stoichiometric excess of reagents,
expensive coupling reagents, waste production and low yields.
Over the past decades, the transition metals [4] and metal-free
[5] catalytic CAC bond cleavage for the synthesis of amide have
been developed to improve the above issues. Three strategies have
been recently reported to cleave the CAC single bonds: (1) devel-
oping functional fragments to increase CAC single bond reactivi-
ties; [6] (2) finding special catalytic systems to assist CAC single
bonds by decreasing activation energy; [7] (3) designing chelation
activated method to increase reactivities of CAC bond [8].
Although the great methods have been improved in cleavage of
CAC bonds, some developed protocols face the limited substrate
scopes, expensive transition-metal catalysts and the harsh reaction
conditions2 (Scheme 1).
The synthesis of pyridyl benzamides have been a booming topic
and have had rapid advancement. Recently, the copper catalyzed
aerobic oxidation [9] and oxygenation reaction with molecular oxy-
gen has had rapid development. Considering the significance of N-
heterocyclic amides in different areas, the development of efficient
synthetic approaches for their synthesis of ketones through C
(CO)AC bond cleavage remains challenging tasks. Last several years,
pyridyl benzamides have received considerable attention. In 2014,
Huang et al. reported copper(I)-catalysed oxidative CAN coupling
of 2-aminopyridine with terminal alkynes featuring bond cleavage
promoted by visible light [11]. Subsequently, an elegant work on
Cu-catalyzed aerobic oxidative C(CO)AC bond cleavage of pheny-
lacetic acids have been developed [12]. Moreover, Ye group also dis-
closed a Ce(III)-catalyzed protocol to afford pyridyl benzamides [13].
Despite the fact that several elegant examples have been described,
new pathways for ketones promoted CAC bond formation are still
highly desirable. In very recent times, a few examples about ketones
have been reported to cleave C(CO)-C bond under O2 atmosphere
[14]. Inspired by previous reported protocols and thoughts, we
reported a novel strategy for N-substituted benzamides formation
⇑
Corresponding authors.
E-mail addresses: hgs@lzu.edu.cn (G. Huang), yqzhang@iccas.ac.cn (Y. Zhang).
These authors contributed equally to this work.
2
delete (scheme 1)
C(CO)–C(alkyl) bond cleavage
y
3
https://doi.org/10.1016/j.tetlet.2021.153199
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

H. Ma, G. Lu, B. Han et al.
Tetrahedron Letters 75 (2021) 153199
Table 1
Optimization of reaction conditionsa.
Entry
Catalyst
Ligand
Solvent
Additive
Yield (%)b
1
2
3
CuCl
CuBr
CuCl2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Py
Py
Py
Py
Py
Py
Py
Py
PhCl
PhCl
PhCl
PhCl
PhCl
DMSO
DMF
Xylene
PhCl
PhCl
PhCl
56
nd
35
nd
4c
5d
6
17
Trace
Trace
50
39
28
7
8
9e
10
11
Py
1,10-Phen
35
L-Proline
Scheme 1. Different transformations for pyridyl benzamides.
12
13
14
15
16
CuCl
CuCl
CuCl
CuCl
CuCl
none
Py
Py
Py
Py
PhCl
PhCl
PhCl
PhCl
PhCl
45
78
12
27
39
DMAP
HOAc
Na2CO3
NaHCO3
from aryl ketones and 2-aminopyridine under Cu(I)-catalyzed aero-
bic oxidative in the presence of DMAP1. DMAP is one of the most
important organic mild bases, which can promote the cleavage of
CAC bond efficiently. Fortunately, numerous aryl ketones have been
demonstrated to be active substrates in this novel strategy, thus
greatly broaden the substrate scope. A novel mechanism and the
detailed mechanistic studies are also presented.
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (20 mol%), ligand
(0.6 mmol) and additive (0.2 mmol) in solvent (2 mL) was stirred at 130 °C for 18 h.
b
Isolated yields.
Under N2 atmosphere.
Under air atmosphere.
At 110 °C. Py
c
d
e
= pyridine; 1,10-phen = 1,10-phenanthrolin; DMAP = 4-
We firstly selected acetophenone (1a) and 2-aminopyridine
(2a) as the model substrates to examine various reaction condi-
tions (Table 1). It was found that the catalyst and solvent critically
affect the reaction efficiency. As we can see, copper salts demon-
strated good activities on this novel transformation. The reaction
of 1a (0.2 mmol, 1 equiv) with 2a (0.4 mmol, 2 equiv) was con-
ducted in the presence 0.04 mmol of CuCl as catalyst, 3.0 equiv
of pyridine in PhCl under O2 at 130 °C, and the desired product
(3aa) was obtained in 56% yield (Table 1, entry 1). Then a variety
of copper salts were attempted, the results showed that CuCl was
more efficient than other copper salts such as CuBr and CuCl2
(Table 1, enties 1–3). We also studied whether the reaction could
conduct under N2 or in air atmosphere. The results showed that
O2 was better than N2 and air, and small amount or no product
was detected under air or N2 (Table 1, entries 1, 4–5). When the
solvent was changed into DMSO or DMF, only trace desired pro-
duct 3aa was detected, while xylene gave the desired product in
50% yield, showing that PhCl was the optimal choice (Table 1, entry
6–8). When temperature was decreased to 110 °C, the yield of
desired product 3aa reduced correspondingly (Table 1, entry 9).
Next, we optimized the ligand, the result indicated that pyridine
dimethylaminopyridine.
(Scheme 2, 3aa-3oa). Whether mono methyl acetophenone or
multi methyl acetophenone were all well tolerated in this system
(Scheme 2, 3ba-3da). We found that a variety of halogen-contain-
ing acetophenones are compatible with the reaction conditions,
such as fluorine acetophenone, chlorine acetophenone and bro-
mine acetophenone (Scheme 2, 3ea-3ha). As a challenging sub-
strate, acetophenones bearing NO2-, CF3- and Ph- groups afforded
the corresponding amides in moderate to good yields (Scheme 2,
3ia-3ka). In addition, naphthalene moieties also underwent the
reaction to furnish the corresponding products, affording the corre-
sponding products in 73% and 71% yields respectively (Scheme 2,
3la-3ma). Moreover, other heteroaryl ketones including 1-(2-fura-
nyl)-ethanon, 1-(2-pyridinyl)-ethanon also successfully endured
the reaction to furnish the desired pyridyl-amide products
(Scheme 2, 3na-3oa).
Next, the substrate scope of various 2-aminopyridines was also
investigated by using 1a as a partner (Scheme 3). 2-aminopyridi-
nes with electron-withdrawing group or electron-donating group
on the phenyl ring also could be performed, and yields of corre-
sponding products range from 35% to 83% (Scheme 3, 3aa-3al).
Interestingly, highly fluorinated 2-aminopyridine was also proved
to be reactive (Scheme 3 3aj). As a challenging substrate, 2-
aminopyridine with a nitro substituent was successfully applied
to the reaction (Scheme 3 3ak).
was the superior choice to 1,10-phenanthrolin and
L
-proline
(Table 1, entry 10–12). Among the various additives we screened,
DMAP was the most effective, affording 3aa in the highest yield
of 78% (Table 1, entry 13–16). We speculate that the alkalinity of
the reaction system was enhanced after introduction of DMAP
which was suitable for this reaction. Finally, the optimized reaction
conditions are as follows: acetophenone 1a (0.2 mmol), 2-
aminopyridine 2a (0.4 mmol), CuCl (20 mol%), pyridine (3 equiv),
and DMAP (1 equiv) in PhCl (2 mL) at 130 °C under oxygen.
With the optimized reaction conditions in hand, we then inves-
tigated the substrate scope of the acetophenone derivatives as a
coupling partner (Scheme 2). Both electron-rich and electron-with-
drawing groups on the ring of acetophenone could be performed
smoothly to afford the corresponding products in available yields
In order to further explore possible reaction mechanism, a set of
control experiments were performed (Scheme 4). To examine the
absence of radical involvement, the reaction was performed under
the standard conditions in the presence of di-tert-butylhydroxy-
toluene (BHT) and 2,2,6,6 tetramethylpiperidine-1-oxyl (TEMPO)
as a radical trapping reagent. The oxidation was greatly suppressed
and only a trace amount of 3aa was observed, which might indi-
cate the possibility of a radical mechanism.
1
(Scheme 1).
2

H. Ma, G. Lu, B. Han et al.
Tetrahedron Letters 75 (2021) 153199
Scheme 4. Controlled experiments.
Scheme 5. Plausible mechanistic pathway.
aminopyridine (2a) generate intermediate A by the nucleophilic
addition [16]. In pathway a, superoxide intermediate B is formed
in the presence of Cu salt and oxygen via single electron transfer
(SET). Then, the SET reduction and subsequent protonation of
intermediate B gives hydroperoxide intermediate C [17] by CuI
and [PyH]+. The cleavage of the CAC bond occurred during the rear-
rangement of intermediate C [18], resulting in the desired product
3aa along with aldehyde D and H2O. In pathway b, enamine E is
generated reversibly by the dehydration of intermediate A. Subse-
quently, dioxetane intermediate F is produced from enamine E in a
Cu(II)/oxygen system in the presence of pyridine. Eventually, the
desired product 3aa and byproduct aldehyde D are formed by
the CAC bond and OAO bond cleavage of dioxetane intermediate F.
In summary, a facile and highly efficient method has been suc-
cessfully developed for efficient oxidative cleavage of C(CO)AC
(alkyl) bond to generate N-substituted benzamides. The synthesis
was carried out via copper(I)-catalysed aerobic oxidative of ace-
tophenone and 2-aminopyridine in the presence of DMAP under
mild conditions. A series of structurally diverse products could be
effectively obtained using DMAP as additive in the presence of
CuCl. The usage of inexpensive copper catalyst, broad substrate
scope, mild conditions make this protocol be very practical.
Scheme 2. Substrate scope of the reaction with aryl ketones.
On the basis of the above results and previous reports [15], two
possible reaction pathway was proposed for the reaction of ace-
tophenone with 2-aminopyridine in the synthesis of pyridyl benza-
mides (Scheme 5). Initially, acetophenone (1a) and 2-
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.
Acknowledgments
The authors greatly appreciate the following financial supports:
the National Natural Science Foundation of China (Nos. 21663032,
22061041), PhD research startup foundation of Yan’an University
(YDBK2019-30), Municipal special fund of Yan’an for high-level
talents (2019-29), Open Sharing Platform for Scientific and Techno-
logical Resources of Shaanxi Province (2021PT-004).
Scheme 3. Scope of the reaction with 2-aminopyridines.
3

H. Ma, G. Lu, B. Han et al.
Tetrahedron Letters 75 (2021) 153199
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https://doi.org/10.1016/j.tetlet.2021.153199.
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