Palladium-Catalyzed Ortho-Selective C-H Oxidative Carbonylation of N-Substituted Anilines with CO and Primary Amines for the Synthesis of o-Aminobenzamides

Article abstract of DOI:10.1021/acs.orglett.6b02255

An efficient, one-pot strategy with high selectivity and high atom economy for the synthesis of o-aminobenzamides has been developed via palladium-catalyzed ortho-selective C-H oxidative carbonylation of N-substituted anilines with CO and primary amines. A wide range of N-substituted anilines and primary amines can be tolerated in this transformation to afford the corresponding o-aminobenzamides in moderate to excellent yields under mild conditions.

Full text of DOI:10.1021/acs.orglett.6b02255

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Ortho-Selective C−H Oxidative Carbonylation of
N‑Substituted Anilines with CO and Primary Amines for the Synthesis
of o‑Aminobenzamides
Xiaopeng Zhang,* Shuxiang Dong, Xueli Niu, Zhengwei Li, Xuesen Fan, and Guisheng Zhang*
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang
453007, P. R. China
S
* Supporting Information
ABSTRACT: An efficient, one-pot strategy with high
selectivity and high atom economy for the synthesis of o-
aminobenzamides has been developed via palladium-catalyzed
ortho-selective C−H oxidative carbonylation of N-substituted
anilines with CO and primary amines. A wide range of N-
substituted anilines and primary amines can be tolerated in this
transformation to afford the corresponding o-aminobenza-
mides in moderate to excellent yields under mild conditions.
alladium-catalyzed oxidation carbonylation reactions with
CO have proven to be one of the most important methods
intermediate through palladium-catalyzed ortho-selective C−H
bond carbonylation of N-alkylanilines.2h Subsquently, o-amino-
benzoates were successfully prepared via the palladium-
catalyzed C−H bond oxidative carbonylation of N-alkylanilines
in the presence of an alcohol by Guan and Lei, respectively.12
To the best of our knowledge, the ortho-selective C−H
oxidative carbonylation of N-substituted anilines with amines
leading to o-aminobenzamides has not been developed.
Inspired by Guan’s and Lei’s work, we conjectured that o-
aminobenzamides are also likely to be obtained by the
palladium-catalyzed ortho-selective C−H bond oxidative
carbonylation of N-substituted anilines in the presence of an
amine. Here, we present an efficient approach with high
selectivity and high atom economy to o-aminobenzamides via
the palladium-catalyzed ortho-selective C−H oxidative carbon-
ylation of commercially available N-substituted anilines with
CO and primary amines (Scheme 1).
P
for the synthesis of many carbonyl-containing compounds such
as carboxylic acids and their various derivatives.1 In recent
years, considerable attention has been focused on the
palladium-catalyzed carbonylation of C−H bonds in the
presence of CO, and much progress has been made in this
field.2 Despite these achievements, the direct C−H carbon-
ylation on the aromatic ring of aromatic amines in the presence
of amines affording the corresponding amides still remains
unexplored because the exploration of efficient directing groups
and efficient catalytic systems to suppress the competitive
carbonylation of amines to ureas during the intermolecular
aminocarbonylation of aryl C(sp2)−H exhibits outstanding
challenges.
O-Aminobenzamides and their derivatives have attracted
special research interest due to their remarkable applications as
important reactive intermediates in organic synthesis.3 In
addition, they also find utilization in medicinal chemistry due
to their biological activities such as antimicrobial activity,3i
antithrombotic activity,4 glycogen phosphorylase inhibition,5
and thyroid-stimulating hormone receptor (TSHR) antago-
nistic activity.6 The main methods for the synthesis of these
compounds involve the ring opening of isatoic anhydride,6,7
coupling of anthranilic acid with amines,6,8 N-arylation between
2-bromobenzenamine and benzonitrile,9 the amidation of
alcohols with 2-aminobenzonitrile,10 or N-Fries rearrangement
of N-carbamoyldiarylamines.11 However, these methods
generally suffer from limitations such synthetic precursors
that are not easily accessible, low atom economy, and
sometimes substrate generality. Thus, the development of a
facile and efficient strategy for the synthesis of o-amino-
benzamides is highly desirable. In 2012, Guan reported a novel
approach to isatoic anhydrides via an anthranilic acid
We set out our studies with the screening of reaction
conditions between N-methylaniline (1a) and n-butylamine
(2b) (Table 1). To our delight, treatment of 1a with 2.0 equiv
of 2b in CH3CN under a balloon pressure of CO with
Cu(OAc)2 as the oxidant and KI as the additive afforded the
desired product 3b in 51% yield (Table 1, entry 1); in addition,
Scheme 1. Palladium-Catalyzed Ortho-Selective C−H
Oxidative Carbonylation of N-Substituted Anilines
Received: August 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02255
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Letter
a
Table 1. Reaction Optimization for the C−H
Scheme 2. Scope of Amines
a
Carbonylation
b
entry
oxidant
solvent
MeCN
additive
KI
yield (%)
1
2
3
4
5
6
7
8
9
Cu(OAc)2
O2
51
39
0
MeCN
KI
CuCl2
MeCN
KI
CuBr2
MeCN
KI
0
K2S2O8
MeCN
KI
0
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2/O2
Cu(OAc)2/O2
Cu(OAc)2/O2
tol
KI
49
45
42
50
53
69
78
78
54
DMF
KI
DMSO
KI
1,4-dioxane
MeCN/tol
MeCN/tol
MeCN/tol
MeCN/tol
MeCN/tol
KI
c
10
11
12
13
14
KI
c
c
c
c
,
,
,
,
d
d
d
d
KI/AcOH
KI/AcOH
KI/AcOH
KI/AcOH
,
,
,
e
e
e
,
f
,g
a
Standard reaction conditions: 1a (1.5 mmol), 2b (3.0 mmol),
Pd(OAc)2 (0.075 mmol), Cu(OAc)2 (3.0 mmol), KI (0.3 mmol), and
b
solvent (8.0 mL) under 1 atm of CO at 70 °C for 18 h. Isolated
c
d
e
yields. CH3CN/tol (1:1). AcOH (4.5 mmol). CO/O2 (5:1) 1 atm.
f
g
Cu(OAc)2 (2.3 mmol). Cu(OAc)2 (1.5 mmol).
over 20% yields of both 1,3-dibutylurea and 3-butyl-1-methyl-1-
phenylurea together with a small amount of N-methylanthra-
nilic acid and isatoic anhydride could be detected in the
reaction system. Further screening of oxidants such as O2,
CuCl2, CuBr2, and K2S2O8 revealed that O2 was less effective
than Cu(OAc)2, while CuCl2, CuBr2, and K2S2O8 were all
totally ineffective (Table 1, entries 2−5). Subsequently, the
effects of different solvents were investigated, and the results
indicated that the mixed solvent of CH3CN/toluene gave the
best result (Table 1, entriey 10) but other solvents such as
toluene, DMF, DMSO, and 1,4-dioxane were also effective
(Table 1, entries 6−9). We were pleased to find that the
desired product 2b could be increased significantly when 4.5
mmol of AcOH was added to the reaction system (Table 1,
entriey 11). The role of AcOH here is believed to suppress the
competitive self- and cross-carbonylation of free amines by
tuning their concentration. Subsequently, the combination of
Cu(OAc)2/O2 as oxidant was tested, and it was found that this
combination was more beneficial to the present carbonylation
reaction (Table 1, entriey 12). On this basis, the load of
Cu(OAc)2 was further optimized, and it was found that 2.3
mmol could satisfy this transformation well (Table 1, entries 13
and 14).
With the optimized reaction conditions in hand, we next
evaluated the scope and efficiency of the reaction with a series
of primary amines. As shown in Scheme 2, the present catalytic
system showed good tolerance to a variety of aliphatic and
aromatic amines, affording the desired o-aminobenzamides in
moderate to excellent yields. Generally, the amines with low
steric hindrance were more effective than those with high steric
hindrance (3d, 3t), suggesting that this method was sensitive to
steric factors. The electron effect was also observed in this
transformation. Both electron-withdrawing and -donating
groups on the benzene ring of substituted anilines were
a
Reaction coditions: 1a (1.5 mmol), 2 (3.0 mmol), Pd(OAc)2 (0.075
mmol), Cu(OAc)2 (2.3 mmol), KI (0.3 mmol), CO/O2 (5:1) 1 atm,
AcOH (4.5 mmol) in MeCN/toluene (4.0 mL/4.0 mL) at 70 °C for
b
18 h. Isolated yields. Amine was added dropwise for 9 h.
tolerated well to produce the corresponding products in good
to excellent yields. On the whole, the electron-rich substrates
showed better reactivity (3m, 3n, 3o, 3p) compared with those
electron-deficient ones (3g−k). Thus, the reaction failed to
proceed with 2-chlorobenzenamine most probably due to its
negative effects of both steric and electron factors (3g). It is
noteworthy that the present carbonylation reaction proceeded
poorly with 4-methoxybenzenamine and benzylamine. This is
because the carbonylation of amines themselves to the
corresponding symmetrical ureas was the overwhelming
reaction, most probably due to their high reactivity. For this
reason, we added these amines dropwise into the reactor to
suppress the competitive self-carbonylation side reaction and
succeeded in obtaining the desired o-aminobenzamides with
satisfactory yields (3p, 3q). In addition, thiazol-2-amine was
B
DOI: 10.1021/acs.orglett.6b02255
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Letter
chosen as a representative of heterocyclic amines to test its
applicability and found it worked smoothly with the above
titration method (3s). Finally, we also used diethylamine as a
representative aliphatic secondary amine; unfortunately, the
reaction failed to proceed, probably due to its high steric
hindrance and weak reactivity (3t).
Subsequently, to further expand the scope of this method-
ology, we applied the present catalytic system to a variety of N-
substituted anilines (Scheme 3). The results indicated that
substituted anilines toward valuable o-aminobenzamides has
been developed. This methodology demonstrated good func-
tional-group tolerance, high selectivity, and high atom
economy. The carbonylation reaction of N-substituted anilines
could proceed efficiently with CO and commercially available
primary amines at 1 atm pressure in a one-pot manner,
affording the corresponding o-aminobenzamides in moderate to
excellent yields.
ASSOCIATED CONTENT
* Supporting Information
■
a
Scheme 3. Scope of N-Substituted Anilines
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02255.
General experimental procedures, spectral data, and
NMR spectra for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
* E-mail: zhangxiaopengv@sina.com.
* E-mail: zgs6668@yahoo.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Program for
Changjiang Scholars and Innovative Research Team in
University (IRT1061), Program for Innovative Research
Team in Science and Technology in University of Henan
Province (15IRTSTHN003), the Education Department of
Henan Province, China (2013GGJS-059, Young Backbone
Teachers Training Fund), and Henan Normal University
(2011-8, Young Backbone Teachers Training Fund).
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Reaction coditions: 1 (1.5 mmol), 2b (3.0 mmol), Pd(OAc)2 (0.075
mmol), Cu(OAc)2 (2.3 mmol), KI (0.3 mmol), CO/O2 (5:1) 1 atm,
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the carbonylation reaction. Generally, the N-substituted anilines
with low hindrance (3bb,bh,bi,bk,bl) were proved to possess
higher activity than those with high steric hindrance (3bc−
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yields (50%−70%) than the latter (0−27%). Both N-
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products in 50−62% yields (3bh,bi, 3bk,bl), which indicated
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We also used N-unsubstituted aniline and found significant
amounts of symmetrical diphenylurea and dibutylurea rather
than the desired o-aminobenzamide were formed (3bf).
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for ortho-selective C−H oxidative carbonylation of N-
C
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