Copper-Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amides

Article abstract of DOI:10.1021/acs.orglett.7b02326

Cu₂O/N,N′-bis(thiophen-2-ylmethyl)oxalamide is established to be an effective catalyst system for Goldberg amidation with inferior reactive (hetero)aryl chlorides, which have not been efficiently documented by Cu-catalysis to date. The reaction is well liberalized toward a variety of functionalized (hetero)aryl chlorides and a wide range of aromatic and aliphatic primary amides in good to excellent yields. Furthermore, the arylation of lactams and oxazolidinones is achieved. The present catalytic system also accomplished an intramolecular cross-coupling product.

Full text of DOI:10.1021/acs.orglett.7b02326

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and
Amides
Subhadip De,† Junli Yin,‡ and Dawei Ma*,†,‡
†State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu Shanghai 200032, China
‡School of Physical Science and Technology, ShanghaiTech, 319 Yueyang Road, Shanghai 200031, China
S
* Supporting Information
ABSTRACT: Cu2O/N,N′-bis(thiophen-2-ylmethyl)-
oxalamide is established to be an effective catalyst system for
Goldberg amidation with inferior reactive (hetero)aryl
chlorides, which have not been efficiently documented by
Cu-catalysis to date. The reaction is well liberalized toward a
variety of functionalized (hetero)aryl chlorides and a wide
range of aromatic and aliphatic primary amides in good to
excellent yields. Furthermore, the arylation of lactams and oxazolidinones is achieved. The present catalytic system also
accomplished an intramolecular cross-coupling product.
ransition metal catalyzed N-arylation of amides is one of
suitable ligands and reaction conditions for this reaction was
Tthe most proficient and convenient methods for preparing conducted, and the results are disclosed here.
As indicated in Table 1, using 4-chloroanisole and benzamide
N-aryl amides, which play a significant role in pharmaceutical,
agrochemical, and material science.1 The humbled nucleophil-
icity of amides (electron-withdrawing carbonyl groups)
comparable to amines make them challenging partners in
metal-catalyzed cross-coupling reactions. In recent decades, a
number of Pd-,2−6 Ni-,7 and Cu-8−13 based catalytic systems
have been successfully developed for this important trans-
formation. Although less expensive and reactive (hetero)aryl
chlorides have been found to be workable under some Pd- and
Ni-catalyzed coupling reactions with amides,5−7 they are still
problematic substrates when less expensive copper/ligand
catalytic systems were used. In 2001, Buchwald and co-
workers12 for the first time attempted amidation with aryl
chlorides under the catalysis of CuI and 1,2-diamine ligands.
However, only four examples were demonstrated, in which aryl
chlorides (4.0 equiv) were used as both substrates and solvents.
Afterward, the same protocols have been followed by Wei et
al.13a and Cossy et al.13b to achieve the amidation of heteroaryl
or aryl chlorides. Obviously, the requirement of more excess
(hetero)aryl chlorides as both reactants and solvents limits the
synthetic usage of these copper-catalytic methods. Thus,
discovery of more powerful Cu-based catalytic systems that
allow coupling of amides and (hetero)aryl chlorides with good
generality and operability is highly desirable.
as the exemplary substrate combination, we initially screened
ligands with 10 mol % CuI as a catalyst, K3PO4 as a base in
DMSO (2 M) at 130 °C for 24 h. After screening several
substituted N,N′-bisoxalamide symmetrical ligands L1−L4,
which exposed outstanding ability in our previous studies,14a−d
up to 36% yield was achieved due to poor conversion (Table 1,
entries 1−4). Later, we moved to screening unsymmetrical
oxalic diamides L5 and L6, but unfortunately the outcome was
not considerable (Table 1, entries 5 and 6). Recently, our group
discovered that only 1−2 mol % each of Cu2O and N,N′-bis[(2-
furyl)methyl]oxalamide (BFMO) are enough to synthesize N-
arylated heterocycles from aryl bromides and iodides.14e We
then carried out the amidation of 4-chloroanisole and
benzamide with 10 mol % CuI/BFMO (L7) in DMSO,
(Table 1, entry 7) which revealed that the yield of the reaction
could be surprisingly increased to 72%; at the same time, we
assumed that furyl oxygen might have a crucial role in
promoting the reaction. In response to this exciting result, we
then customized N,N′-bis(thiophen-2-ylmethyl)oxalamide
(BTMO), L8, which is a similar to L7 containing a sulfur in
the aromatic ring, starting from commercially available 2-
thiophene-methylamine and performed the coupling reaction.
A slight improvement of the yield was observed (Table 1, entry
8). Next, in accordance with our earlier BFMO promoted
coupling report, we changed the catalyst from CuI to Cu2O. It
was revealed that a 78% yield was afforded using L8 whereas L7
is giving only a 70% yield of our expected amide-coupling
product (Table 1, entries 9 and 10). Hence, we considered that
In 2015, we reported that some biaryl or aryl and alkyl
substituted oxalic diamides are effective ligands that enable Cu-
catalyzed coupling of (hetero)aryl chlorides with amines,
phenols, and hydroxide to proceed under relatively mild
conditions.14 Based on these studies, we envisioned that the use
of an appropriate oxalic diamide as the ligand would probably
allow us to solve the long-lasting problem in Cu-catalyzed
amidation of (hetero)aryl chlorides. Accordingly, exploration of
Received: July 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02326
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
L10 afforded the coupling product in 82% yield, while other
modified ligands are not effective for this coupling reaction
(Table 1, entries 19−21). To check the ligand efficiency we
carried out a reaction with L12, which contained no
heteroatom in the phenyl ring. The reaction became sluggish,
and the yield sharply decreased to 35% (Table 1, entry 22).
This result demonstrated that the heteroatom in the aromatic
ring must have a great impact to coordinate and further stabilize
the Cu-complexes in the catalytic cycle.
Table 1. Cu2O-Catalyzed Coupling of 4-Chloroanisole with
Benzamide under the Assistance of Different Ligands
a
Later, to verify the role of ligands, we performed a coupling
reaction without the aid of any ligand (Table 1, entry 23), and
it was determined that the ligand greatly impacts this coupling
reaction. Subsequently, considering L8 as suitable ligands, we
tested the reaction using different Cu-catalysts in t-BuOH
solvent, but yields sharply decreased (Table 1, entries 24−26).
By studying various solvents and bases (Table 1, entries 27−
33), and even under neat conditions (Table 1, entry 30), t-
BuOH and K3PO4 were found to be the best combination for
this coupling reaction.
Under these optimistic conditions, we achieved 53% and
67% yields when the reaction was executed using 5 mol %
Cu2O/L8 at 130 °C and 10 mol % Cu2O/L8 at 120 °C,
respectively (Table 1, entry 34 and 35). The conversion was
very poor in the case of N,N′-dimethyl-1,2-cyclohexanediamine
(DMCyDA) and N,N′-dimethylethylenediamine (DMEDA) as
the ligands (Table 1, entries 36 and 37).
b
b
entry
ligand
yield (%)
entry
ligand
yield (%)
c
1
L1
L2
L3
L4
L5
L6
L7
L8
L7
L8
L7
L8
L1
L2
L3
L4
L5
L6
L9
14
23
36
20
5
20
21
22
23
L10
L11
L12
no
82
23
35
0
c
2
c
3
c
4
With reliable and optimal conditions in hand, we then
examined the substrate scope using a variety of (hetero)aryl
chlorides with different amides, as encapsulated in Scheme 1. A
series of benzanilides (3b−f), along with a few bioactive small
benzanilides,1e were synthesized in 74−92% isolated yields. In
order to exhibit advantages of this catalytic system, we
accomplished reactions where we could probe the electronic
and steric nature of the aryl chlorides. Noticeably, 3-thiophenyl
and 2-pyridinyl chlorides underwent smooth reactions to afford
products 3g−i in up to 81% yield. Changing amides from
benzamide to other aromatic amides and aliphatic amides was
also possible, leading the formation of substituted benzamides
3j−o in good to excellent yields. In order to make our strategy
practically viable, two reactions were conducted with 4 mmol
scales under our standard conditions, which afforded 3d and
3m in 72% and 71% yields, respectively. Notably, coupling of
1,2-dichlorobenzene and benzamide selectively gave mono-
amidation coupling product 3n in 73% yield. Our catalytic
system is also well tolerated in the coupling of nicotinamide
and 2-thiophenecarboxamide, providing the corresponding
products 3p and 3q in 83% and 79% yields, respectively.
When aliphatic amides were used, a broad range of N-arylated
secondary amides, including N-arylated cyclopropane-
carboxamide (3r), cyclopentanecarboxamide (3s), thiophene-
acetamide (3t), 2-phenylacetamide (3u), acetamide (3v),
trifluoroacetamide (3w), and propionamides (3x and 3y),
could be obtained. However, to our disappointment, using this
particular optimized set of conditions, the amidation reaction of
acyclic secondary amides with aryl chlorides was not successful,
probably due to the larger steric hindrance of acyclic secondary
amides compared to primary amides.
c
c
5
24
L8
38
35
33
44
45
50
15
21
39
52
53
67
5
c
d
6
8
25
L8
c
e
7
72
75
70
78
47
87
11
25
15
21
trace
9
26
L8
c
f
8
27
L8
g
9
28
L8
h
10
11
12
13
14
15
16
17
18
19
29
L8
i
30
L8
j
31
k
L8
32
L8
l
33
L8
m
34
L8
n
35
L8
36
37
L13
L14
13
79
a
General conditions: 1a (1 mmol), benzamide (1.5 mmol), Cu2O (0.1
mmol), ligand (0.1 mmol), K3PO4 (2.0 mmol), DMSO (0.5 mL, for
entries 1−10), or t-BuOH (0.5 mL, for entries 11−26, 31−37). The
yield was determined by H NMR analysis of crude products using
b
1
c
d
CH2Br2 as the internal standard. CuI as the catalyst. CuBr as the
e
f
g
catalyst. Cu(OAc)2 as the catalyst. DMF as the solvent. DMA as the
h
i
j
solvent. NMP as the solvent. Neat conditions. K2CO3 as the base.
k
l
m
Cs2CO3 as the base. KOH as the base. Cu2O (5 mol %), ligand (5
mol %). The reaction was conducted at 120 °C.
n
Cu2O/L8 might be the better choice for further studies.
Encouraged by this result, we decided to change the solvent
from DMSO to t-BuOH and conducted the coupling reaction
at 130 °C (Table 1, entries 11 and 12). To our delight, it was
observed that L8 gave an 87% yield of our anticipated product
3a (Table 1, entry 12).
Next, we explored the possibility for coupling (hetero)aryl
chlorides with lactams and oxazolidinones because various
substituted N-arylated lactams and oxazolidinones have shown
important biological activities. As depicted in Scheme 2, under
the standard conditions, a series of para-substituted aryl
chlorides containing either electron-releasing or electron-
With these conditions, we then tried to screen other
oxalamide ligands (L1 to L6), but no momentous improvement
in conversion was observed (Table 1, entries 13−18). We also
modified the ligand structure and synthesized symmetrical L9
and unsymmetrical L10 and L11 from 2-thiophene-
methylamine and furfurylamine. Under the same conditions,
B
DOI: 10.1021/acs.orglett.7b02326
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Scope of Cu2O/BTMO Catalyzed Coupling
Reaction of (Hetero)aryl Chlorides with Amides
Scheme 2. Scope of Cu2O/BTMO Catalyzed Coupling
a
Reaction of (Hetero)aryl Chlorides with Lactams and
a
Oxazolidinones
a
General conditions: 1 (1 mmol), 4 (1.5 mmol), Cu2O (0.1 mmol),
BTMO (0.1 mmol), K3PO4 (2.0 mmol), t-BuOH (0.5 mL), 130 °C,
24 h.
a
General reaction conditions: 1 (1 mmol), amide 2 (1.5 mmol), Cu2O
Scheme 3. Cu-Catalyzed Intramolecular Amidation of Aryl
Chloride
(0.1 mmol), BTMO (0.1 mmol), K3PO4 (2.0 mmol), t-BuOH (0.5
mL), 130 °C, 24 h.
withdrawing groups afforded complete conversion in coupling
with 2-pyrrolidinones and 2-oxazolidinone (5a−g). When more
bulky six- and seven-membered lactams were used, the coupling
became sluggish and decreased yields were observed (5h−j). A
polysubstituted 2-pyrrolidinone also provided us with a
satisfactory outcome with a 77% isolated yield (5k).
Remarkably, under the optimized conditions, 2-hydroxypyr-
idine selectively delivered N-arylated product 5l with 4-
chlorotoluene; no O-arylated product was observed.15 The
monoarylated product 5m could be obtained in 73% yield when
2-imidazolidone was used. Some enantioenriched 2-pyrrolidi-
nones and oxazolidinone were also applicable, delivering the
related amidation products 5n−p in moderate yields.
Scheme 4. Possible Mechanism
To show the versatility of this catalytic system, an
intramolecular version of the N-arylation protocol was
investigated (Scheme 3). Delightfully, we observed that 2-(2-
chlorophenyl)acetamide 6 afforded 2-oxindole 7 in 75% yield.
A tentatively proposed mechanism for the present coupling
reaction is shown in Scheme 4. We thought that, with
treatment of K3PO4, Cu2O might react with BTMO to afford
Cu(I) complex A, in which the strong electron-donating ability
of the ligand could make this complex very active toward the
oxidative addition with an aryl chloride. The oxidation addition
product, Cu(III) complex B, might undergo a ligand exchange
with an anion generated from the amide to provide complex C.
Reductive elimination of C would deliver the aryl amide and
regenerate the catalytic species A.
In conclusion, we have demonstrated that N,N′-bis-
(thiophen-2-ylmethyl)oxalamide (BTMO) is a powerful
promoter for Cu-catalyzed Goldberg-amidation coupling with
(hetero)aryl chlorides. Utilizing our catalytic system, we were
able to synthesize a wide variety of N-arylated amides, lactams,
and oxazolidinones. Further exploration of this strategy and
mechanistic studies are currently underway in our laboratory.
C
DOI: 10.1021/acs.orglett.7b02326
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Pawar, G. G.; Kumar, S. V.; Jiang, Y.; Ma, D. Angew. Chem., Int. Ed.
2017, DOI: 10.1002/anie.201701690.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02326.
■
S
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Experimental procedures, spectra data, and copies of all
new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: madw@sioc.ac.cn.
ORCID
Dawei Ma: 0000-0002-1721-7551
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful to Chinese Academy of Sciences
(supported by the Strategic Priority Research Program, Grants
XDB20020200 and QYZDJ-SSW-SLH029) and the National
Natural Science Foundation of China (Grant 21621002) for
their financial support. S.D. thanks the CAS President’s
International Fellowship Initiative (PIFI) for postdoctoral
researcher.
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