Chemoselective: N -arylation of aminobenzamides via copper catalysed Chan-Evans-Lam reactions

Article abstract of DOI:10.1039/c7ob02491f

Chemoselective N-arylation of unprotected aminobenzamides was achieved via Cu-catalysed Chan-Evans-Lam cross-coupling with aryl boronic acids for the first time. Simple copper catalysts enable the selective arylation of amino groups in ortho/meta/para-aminobenzamides under open-flask conditions. The reactions were scalable and compatible with a wide range of functional groups.

Full text of DOI:10.1039/c7ob02491f

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Chemoselective N-arylation of Aminobenzamides via Copper
Catalysed Chan−Evans−Lam Reactions
Shuai Liu,a Weisai Zu,a Jinli Zhang*a,b and Liang Xu*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
O
Chemoselective N-arylation of unprotected aminobenzamides was
achieved via Cu-catalysed Chan−Evans−Lam cross-coupling with
aryl boronic acids for the first time. Simple copper catalysts enable
the selective arylation of amino groups in ortho/meta/para-
aminobenzamides under open-flask conditions. The reactions
were scalable and compatible with a wide range of functional
groups.
Me
N
HN
Me
H
N
NH
N
HN
O
N
N
H2N
N
NH
N
CF3
Nilotinib
N
antileukemia
DNMT inhibitor
N
Me
Aromatic C−N bonds are prevalent across a wide range of
synthetic
Previous work: selective cross-couplingwith electrophiles
important
organic
compounds,
including
O
Ar-X, Cu cat.
Ar-X, Pd cat.
intermediates, organic materials, pharmaceutical and natural
products. Therefore, the development and application of
methods to construct C(aryl)–N bonds have long been one of
the most important research areas in organic chemistry.
In the last two decades, a plethora of transition-metal-
catalysed C–N cross-coupling reactions have achieved
remarkable progress and been widely practiced.1 Among
these, the Cu-catalysed Ullmann2 and Pd-catalysed Buchwald-
Hartwig3 amination reactions generally couple nucleophilic
nitrogen atoms with electrophilic partners such as aryl halides.
In contrast, Cu-catalysed/mediated Chan−Evans−Lam (CEL)4
reactions couple two nucleophiles, usually an amino group and
an organoboron compound, under oxidative conditions. The
CEL reactions were developed independently by Chan, Evans
and Lam in 1998, being characterized by low cost of catalysts
and ligands, high tolerance towards aerobic environment and
simple reaction conditions.5 This inspired the following
intensive investigations and significant improvement in this
field, therefore mutually reinforcing the defining
characteristics of such reactions. Nowadays, different reaction
systems are still
Ar
N
H
H2N (Ph)
H2N
NH2
O
Ar
(Ar)2I
X
O
NH2
h)
(P
N
H
Cu cat.
This work: selective oxidative cross-coupling with nucleophiles
Ar
Ar-B(OH)2, Cu cat.
H2N
N
H
NH2
NH2
Open flask, Ligand-free
O
O
Room temperature, Scalable
Scheme 1 Representative bioactive N,N’-discriminated diarylated aminobenzamides
and strategic synthesis to mono-arylated aminobenzamides
being continuously developed to improve the reactive
efficiency and broaden the substrate scope.6
Despite such progress, the CEL reactions have been rarely
applied in the chemoselective C−N cross-coupling reactions of
aryl dinucleophiles,7,8 which are usually accomplished by
Ullmann and Buchwald-Hartwig reactions.9 More specifically,
the N,N’-discriminated diarylated aminobenzamides constitutes a
common structural motif in a number of drugs and potential
candidate drugs,10 such as Nilotinib, an approved drug for the
treatment of chronic myelogenous leukemia. This results in efforts
on the selective arylation of unprotected aminobenzamides. In fact,
the aminobenzamides could be selectively arylated with
electrophilic coupling partners, as demonstrated by Buchwald
group9a and Zeng group11, with aryl halides and diaryliodonium
salts, separately.
In contrast, although aniline and benzamide have been two of
the most widely-used nitrogen sources4 in CEL reactions separately,
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chemoselective CEL cross-coupling between organoboron NMR and X-ray diffraction analysis (Scheme 2, CCDC: 1563817).
compounds and the dinucleophilic aminobenzamides have never The yield of 3a was improved to 90% upon utilizing CuCl as catalyst
been realized, to the best of our knowledge. In combination with (Table 1, entry 3). Further screening of other reactive parameters
our ongoing interest in the selective decoration of di- and led to no better results. Other solvents such as DCM and THF
polynucleophiles,12 this situation inspired our efforts on selective turned out to be invalid for this transformations (Table 1,
arylation of aminobenzamides via facile oxidative CEL protocol, entries 1, 11-13). Notably, concentrated solution and elevated
which might offer complementary opportunities in decorating such temperature were detrimental, decreasing the yield of target
type of feedstock. Herein, we disclose our results on the Cu- 3a (Table 1, entries 9, 10). In brief, 90% of chemoselective N-
catalysed chemoselective CEL N-arylation reactions between arylated product 3a, was isolated when 2-aminobenzamide was
aminobenzamides and aryl boronic acids. The aniline moiety was stirred with 1.5 equivalent of phenylboronic acid in aerobic
consistently
preferentially
arylated
for
either
2- MeOH at room temperature for 12 hours, using simple 15 mol%
aminobenzamides that benefited from chelation assistance or 3-/4- of CuCl and 0.5 equivalent of TEA.
aminobenzamides. In addition, the reactions could be facilely and
efficiently accomplished under ligand-free and aerobic conditions at
room temperature.
Table 1. Optimization of reaction conditions[a]
Entry
1
Catalyst
Cu(OAc)2
Cu(OTf)2
CuCl
Base
TEA
Solvent
DCM
Yields (%)[b]
N.R.
2
TEA
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DCM
34
90
3
TEA
4
CuCl
-
63
5
CuCl
K2CO3
Na2CO3
KHCO3
DBU
TEA
81
6
CuCl
75
7
CuCl
68
8
CuCl
68
9
CuCl
66[c]
24[d]
N.R. (75%)[e]
N.R.
N.R.
10
11
12
13
CuCl
TEA
CuCl
TEA
CuCl
TEA
THF
CuCl
TEA
toluene
Scheme 2 Reactions between 2-aminobenzamides and aryl boronic acids
[a]Reaction conditions: 0.5 mmol 1a (1.0 equiv.), 0.75 mmol 2a (1.5 equiv.), 0.075
mmol CuCl (15 mol%), 0.25 mmol bases (0.5 equiv.), r.t., open flask, 12 h.
[b]Isolated yields. [c]MeOH (1.0 mL). [d]70 oC. [e]The isolated yield of PhB(aam).
Under the optimized reaction conditions, various aryl
boronic acids were reacted with 2-aminobenzamide, and the
results were illustrated in Scheme 2. Both electron-rich and -
deficient boronic acids were compatible with such conditions.
Reactions of 3- or 4-substituted compounds bearing methyl,
halides, methoxy and trifluoromethyl groups afforded target
We commenced the studies using 2-aminobenzamide
(anthranilamide, AAM) 1a and phenylboronic acid 2a as reaction
components (Table 1). Transformations were conducted in
open flasks with air as oxidant.13 Firstly, copper-mediated
coupling reactions between 1a and 2a were tried, generating a
complex mixture that contained N-arylation products without
obvious chemoselectivity (Table S1, in Supporting Information).
The attempts to realize the catalysed C−N cross-couplings all
failed due to the easy condensation of PhB(OH)2 with 2-
aminobenzamide, which afforded PhB(aam) as the main product.
Using MeOH as solvent, Cu(OTf)2 as catalyst and triethylamine
(TEA) as base, the reaction provided the arylated product of
aniline moiety 3a other than PhB(aam) in 34% yield (Table 1,
entry 2). The structure of the obtained product was confirmed by
products 3a-3k in 70-86% yields. This cross-coupling also well
tolerated cyano- and vinyl-substituted phenyl boronic acids (3l
and 3m). The compatibility towards these functional groups
enabled the potential application for further transformations.
2,6-Disubstituted compound could also be employed in spite
of the significantly decreased yield due to the steric effect (3n
,
31%). Moreover, 2-aminobenzamide bearing -Me and -Cl
substituents also furnished the corresponding products 3p and
3q selectively. Substitution on N atom of the amide group was
2 | J. Name., 2012, 00, 1-3
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also tolerated, affording 3r in slightly lower yield compared catalysis of cheap copper salts (Scheme 4, Eq. A and D). It should be
with the formation of 3a noted this easily-handled and low-cost CEL reaction could be
Next, selective arylation of 3- or 4-aminobenzamide was directly scaled up to gram scale with only slightly reduced yield
explored In the beginning, the reaction between 4- (Scheme 4, Eq. B).
aminobenzamide and phenyl boronic acid was performed under In addition, the synthesis of unsymmetrically diarylated
.
.
the previously optimized conditions. Unfortunately, no aminobenzamides was accomplished through sequential Cu-
arylated product of aniline was observed. This result indicated catalysed C–N cross-coupling reactions. For example, 3a and 5a
the presence of a chelation assistance effect in the reaction were both competent nucleophiles for the Ullmann reactions,
between 2-aminobenzamide and aryl boronic acids under the leading to diarylated aminobenzamides in 59% and 97% yield,
optimized conditions. Copper cyclometalated species might be separately (Scheme 4, Eq. C and F). The Ullmann/CEL sequence was
formed due to the chelation effect of the adjacent amino and amide also feasible, as exemplified by Eq. D and Eq. E in Scheme 4.9a
groups and enabled the following catalytic transformations, like a
recent result from Baidya group.6b
This situation necessitated the further exploration of another
reaction system for 3- and 4-aminobenzamide. 4-aminobenzamide
4a and phenyl boronic acid 2a were used as reaction
components. Screening of reactive parameters revealed that the
combination of copper thiophene carboxylate (CuTC, 20 mol%), 2,6-
lutidine (1.0 equiv.) and DMF (1.0 mL) gave the best result (Details
of screening were listed in Table S2 in Supporting information). The
chemoselective N-arylated product 5a was obtained in 88% yield
(Scheme 3). In addition, this reaction system was also suitable for
the 3-aminobenzamide, whose product 7a was obtained in 87%
yield. The optimized system was then applied for other substrates.
The application of electron-rich 4-methoxy- and 3,5-dimethyl-
phenyl boronic acid would give 5b and 5d, in 65% and 88%
yields, separately. Electron-withdrawing groups such as Cl, CF3
would affect the efficiency of cross-coupling reaction, leading
to decreased yields. 2-Naphthylboronic acid also worked well
,
giving aim product 7b in 80% yield.
Scheme 4 The applications of the selective CEL reactions
Taking advantage of the adjacent arylamino and amide groups in
2-arylamino benzamide, aryl-substituted heterocycles could be
readily accessible. When 3a was treated with acetyl chloride in
acetic acid, 1-phenylquinazolin-4(1H)-one 11 was isolated in 77%
yield.14 Cyclic ureas such as 1-phenyl-benzo[d]imidazol-2-one 12
was generated in 93% yield via iodosylbenzene-induced Hofmann
rearrangement of 3a.15
Scheme 5 The synthesis of aryl-substituted heterocycles. Reaction conditions: a.
0.3 mmol 3a (1.0 equiv.), 0.9 mmol acetyl chloride (3.0 equiv.), acetic acid (1.0
mL), r.t, open flaks, 3 h; b. 0.3 mmol 3a (1.0 equiv.), 0.45 mmol iodosylbenzene
(1.5 equiv.), dichloromethane (1.5 mL), r.t, open flaks, 2 h.
Scheme 3 Reactions between 3- or 4-aminobenzamides and arylboronic acids
As mentioned above, in the Cu-catalysed Ullmann reactions
between aminobenzamides and aryl halides, the arylation occurred
selectively at the amide groups. Therefore, this CEL coupling
protocol might complement such reactivity, which rendered the
selective arylation of amino or amide group feasible both by the
In conclusion, we have shown for the first time that 2-/3-/4-
aminobenzamides can be efficiently chemoselectively arylated by
virtue of Cu-catalysed oxidative CEL aryl–amino cross-coupling
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protocol tolerates a wide range of functional groups and can be
handled at room temperature under open-flask conditions.
Additionally, in the reactions of 2-aminobenzamides, uncommon
chelation assistance plays vital role in determining the catalytic
activity. This protocol has been successfully utilized in the synthesis
of unsymmetrically diarylated aminobenzamides and substituted
heterocycles. Further extended exploration and utilization of this
protocol are underway in our laboratory.
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This work is financially supported by the National Natural Science
Foundation of China (No. 21603150), Shihezi University (funding to
L. X., Nos. RCZX201543 and CXRC201602), the Program for
Changjiang Scholars and Innovative Research Team in University
(No. IRT_15R46), Yangtze River Scholar Research Project of Shihezi
University (No. CJXZ201601).
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Bharatam, P. Y. S. Lam and P. Das, Org. Biomol. Chem., 2017, 15,
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Conflicts of interest
There are no conflicts of interest to declare.
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Chemoselective N-arylation of unprotected aminobenzamides was achieved via Cu-catalysed
Chan−Evans−Lam cross-coupling with aryl boronic acids for the first time.