Palladium-catalyzed C-H bond carboxylation of acetanilides: An efficient usage of N,N-dimethyloxamic acid as the carboxylate source

Article abstract of DOI:10.1039/c5cc07890c

N,N-Dimethyloxamic acid can be successfully employed as a carboxylate precursor in the palladium-catalyzed direct C-H carboxylation of acetanilides. The reaction proceeds smoothly under mild conditions over a broad range of substrates with high functional group tolerance, affording substituted N-acyl anthranilic acids in moderate to high yields.

Full text of DOI:10.1039/c5cc07890c

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Palladium-catalyzed C-H bond carboxylation of
acetanilides: an efficient usage of N, N-dimethyloxamic
acid as the carboxylate source
Cite this: DOI: 10.1039/x0xx00000x
Yinuo Wu*, Cheng Jiang, Deyan Wu, Qiong Gu, Zhang-Yi Luo and Hai-Bin Luo*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
works,13-15 we report herein that N,N-dimethyloxamic acid, an
N, N-Dimethyloxamic acid can be successfully employed as
carboxylate precursor in the palladium-catalyzed direct C−H
carboxylation of acetanilides. The reaction proceeds smoothly
under mild conditions over a broad range of substrates with
easily obtained reagent,16,17 could act as an efficient carboxylate
agent in the palladium-catalyzed coupling of acetanilides for
obtaining anthranilic acid derivatives (Scheme 2c).
high functional group tolerance, affording substituted
anthranilic acids in moderate to high yields.
N-acyl
Anthranilic acid is an important structural motif found in
various natural products and pharmaceutically chemical
entities.1 It is also known to be crucial synthetic precursor for a
wide range of biologically active compounds including
quinazoline, quinoline, benzoxazinone, and acridinone
alkaloids.2 Traditionally, anthranilic acids are synthesized by
the reduction of 2-nitrobenzoic acids in the presence of metal
catalyst, of which the starting material 2-nitrobenzoic acids are
usually toxic and unstable;3 or the Hofmann rearrangement of
phthalamic acids, in which the products are limited to specific
structures.4 Given the prevalence of anthranilic acid moiety in
medicinally relevant compounds, it would be desirable to
develop a concise and highly efficient method to generate
anthranilic acids.
Scheme 1: Palladium catalyzed C-H bonds functionalization of acetanilides.
Transition-metal-catalyzed
direct
C-H
bond
Inspired by Ge’s work that both the α-oxocarboxylic acids
and oxamic acids could be involved in the palladium catalyzed
cross coupling reaction through a decarboxylation way,17,18 we
functionalization has become a cutting-edge methodology for
the synthesis of structurally similar, yet diversified organic
molecules in recent years.5 Since the pioneer work of Fujiwara
and co-workers,6 C-H bonds carbonylation have been widely
applied in the synthesis of carboxylic acids, esters, amides, and
ketones. A number of directing groups, such as carboxylic
acids,8 hydroxyl groups,9 acetanilides,10 phosphinic acids11 and
oximes12 could be involved in the C–H bonds carbonylation
efficiently. In 2010, Yu and co-workers reported a palladium
catalyzed C-H carboxylation of acetanilides with CO as the
envisioned that
N-acyl-2-aminobenbenzamides could be
generated via a similar mechanism in the palladium catalyzed
cross coupling of acetanilides with oxamic acids. To our
surprise, when we used the N, N-dialkyloxamic acid in the
palladium catalyzed C-H bond activation of acetanilides, we
obtained the N-acyl anthranilic acid as the final product, instead
of the decarboxylated product. We next tested different oxamic
acid derivatives in the coupling. Both the N, N-diaryloxamic
carboxylate donor (Scheme 2a), providing
N-acyl anthranilic
acid derivatives in good yields.7 However, the current
investigations mainly focus on the usage of CO as carboxylate
source. The development of other efficient carboxylate agent
has not been reported yet. In continuation of our previous
acid and
N-monoalkyloxamic acid provided desired product
with low yield while 2-ethoxy-2-oxoacetic acid, oxalic acid,
and 2-amino-2-oxoacetic acid gave no conversion (entries 3-7).
Then we began to explore the reaction conditions with N, N
-
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dimethyloxamic acid as carboxylate agent. A screening of other substituted acetanilides. In particular, the bromo group
metal catalysts revealed that Pd(OAc)2 and Pd(TFA)2 were remained intact during the course of the reaction (14, 15),
applicable catalysts (entries 8-11). The effectiveness of which may potentially offer further structural fine-tuning by
oxidants was also examined and demonstrated that K2S2O8 was using other traditional cross-coupling reactions.19 We also
the most suitable oxidant in this reaction (entries 12-15). carried out the reaction with diacetanilides, only the para
-
Further screening of solvent revealed that 1, 2-Dichloroethane diacetanilides gave the desired product with 56% yield (17).
was the most effective solvent while other solvents gave lower Apart from the acetamido group, other directing amido moieties
conversion (entries 16-18). In addition, the reaction temperature were tested in this ortho-carboxylation reaction, iso-propyl
of 80 °C was found to be optimal. Lowering the reaction groups gave the best results while the tert-butyl and phenyl
temperature decreased the substrate conversion (entries 19-20). moiety gave lower yield of the desired products (18-20)
.
Additives such as TFA, AcOH, and TsOH were added to
Table 2: Scope of acetanilides in the Pd-catalyzed oxidative ortho-carboxylationa
improve the yields (entries 21-23). We were delighted to find
that the yield could get up to 73% in the presence of TFA (0.5
equiv.). We also conducted a control reaction with TFA but
without N, N-dimethyloxamic acid added, which proved that
TFA could not act as a carboxylate donor. The reaction with 5
mol% catalyst was performed and could get 58% yield with a
longer time (entry 24).
COOH
O
10 mol% Pd(OAc)2
OH
NHAc
+
NHAc
Me2N
R
TFA, K2S2O8, DCE
R
O
COOH
COOH
NHAc
COOH
NHAc Me
COOH
NHAc
MeO
NHAc
MeO
Table 1: Scope of Pd-catalyzed oxidative ortho-carboxylation of acetanilidea
1, 73%
COOH
2, 81%
COOH
3, 80%
COOH
4, 76%
COOH
MeO
MeO
NHAc
NHAc
NHAc
NHAc
Entry
1
2
3
4
5
6
7
8
R
Conditions
%yieldb
Me
Me
Me
Me
NEt2
Pd(OAc)2, K2S2O8, DCE, 80OC
Pd(OAc)2, K2S2O8, DCE, 80OC
Pd(OAc)2, K2S2O8, DCE, 80OC
Pd(OAc)2, K2S2O8, DCE, 80OC
Pd(OAc)2, K2S2O8, DCE, 80OC
Pd(OAc)2, K2S2O8, DCE, 80OC
Pd(OAc)2, K2S2O8, DCE, 80OC
Pd(TFA)2, K2S2O8, DCE, 80OC
PdCl2, K2S2O8, DCE, 80OC
46
51
4
5
0
5, 77%
COOH
NHAc
6, 71%
COOH
7, 52%
8, 50%
NMe2
NPh2
NHMe
NH2
OEt
OH
COOH
COOH
NHAc
NHAc
NHAc
Cl
F
0
0
Cl
F
9, 70%
COOH
10, 68%
COOH
NHAc
11, 75%
COOH
12, 63%
COOH
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
50
18
32
9
23
0
9
Pd(CH3CN)2Cl2, K2S2O8, DCE, 80OC
Pd(PPh3)4, K2S2O8, DCE, 80OC
Pd(OAc)2, (NH4)2S2O8, DCE, 80OC
Pd(OAc)2, Ag2CO3, DCE, 80OC
Pd(OAc)2, Cu(OH)2, DCE, 80OC
Pd(OAc)2, BQ, DCE, 80OC
Pd(OAc)2, K2S2O8, diglyme, 80OC
Pd(OAc)2, K2S2O8, DMSO, 80OC
Pd(OAc)2, K2S2O8, Dioxane, 80OC
Pd(OAc)2, K2S2O8, DCE, 100OC
Pd(OAc)2, K2S2O8, DCE, 60OC
Pd(OAc)2, K2S2O8, DCE, TFA, 80OC
Pd(OAc)2, K2S2O8, DCE, TsOH, 80OC
Pd(OAc)2, K2S2O8, DCE, AcOH, 80OC
Pd(OAc)2, K2S2O8, DCE, TFA, 80OC
NHAc
NHAc
NHAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
Br
F3C
F
Br
13, 60%
COOH
NHAc
14, 62%
15, 52%
16, 43%
COOH
COOH
COOH
0
0
NH
NH
NH
21
33
9
42
28
78(73)c
65
67
58d
AcHN
O
O
O
iPr
tBu
Ph
17, 56%
18, 68%
19, 51%
20, 42%
a Reaction conditions: Acetaniline (1.0 mmol), Pd(OAc)2 (10 mol%), K2S2O8
(2.0 mmol), N, N-dimethyloxamic acid (2.0 mmol), TFA (0.5 equiv.), DCE
(2.0 mL) were stirred at 80 °C for 24 h under air. Isolated yields were
reported.
a Reaction conditions: Acetaniline (1.0 mmol), Pd(OAc)2 (10 mol%), Oxidant
(2.0 mmol), oxamic acid 2.0 mmol), solvent (2.0 mL) were stirred for 24 h
under air. GC yields were reported. Isolated yields were reported in the
parentheses. d 5% mol Pd(OAc)2 was used in 48 h.
With the substituted
N-acyl-anthranilic acids in hand, we
(
also explored their potential biological activity (SP, Figure 1).
Tranilast, an anthranilic acids derivative, has been reported
b
c
processing the ability to inhibit the aggregation of
(Aβ) peptides in vitro 20
It has been well known that the
formation and accumulation of aggregations of A peptides in
β-amyloid
.
The scope of this reaction was then investigated under the
preliminary optimized conditions. A range of acetanilides were
β
the brain are critical factors in the development and progression
of Alzheimer’s disease.21 Among the 20 anthranilic acids we
examined and the results are listed in Table 2. The
and methyl substituted acetanilide gave high yields of the
corresponding products ( and ). For the 3-substituted
p-methoxyl
obtained, 10 of them showed better inhibitory activity of β-
amyloid (A ) peptides than that of the positive control
2
3
β
acetanilides, the coupling only took place on the less hindered
side presumably due to the steric hindrance (4 -6, 10, 12,15,16).
It was worth noting that ortho-substituted substrates were
feasible coupling partners in this catalytic system (7, 8, 13).
Fluoro/chloro/bromo substituted acetanilides were compatible
substrates (9–15), although the yields were lower than those of
curcumin (EC50 3.9 ꢀM)22 and compound 3 showed the best
activity.
Control experiments were performed to identify the possible
reaction mechanism (Scheme 2). The 5-membered palladcycle
P1 was prepared and reacted with the acetanilide under
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different conditions.22 The desired product was obtained with K2S2O8, thus completing the catalytic cycle. We also monitored
73% yield using catalytic complex P1 and 76% yield with the existence of N, N-dimethylformamide during the reaction
stoichiometric complex P1, which confirmed that the complex by GC-MS. Yet, other alternative pathways cannot be excluded.
P1 might be the actual intermediate during the catalysis
(Scheme 2, condition A and B). We conducted the reaction catalyzed cross-coupling of acetanilides and N,N
under typical condition but without the Pd catalyst, the N,N dimethyloxamic acid for the direct accessing to anthranilic
In conclusion, we have developed a novel palladium
-
-
dimethyloxamic acid turned to the N, N-dimethylformamide in acids. This is the first example of using N,N-dimethyloxamic
- 23
the presence of S2O8 , but no conversion of the acetanilide acid as carboxylate agent in the C-H bonds carboxylation.
was observed, which proved that the Pd catalyst was necessary Fluoro, bromo, chloro, and methoxy groups at different
for the C-H bond activation (Scheme 2, condition C). When the positions of arene are compatible in this catalytic system. An
reaction was carried with stoichiometric complex P1 but array of substuituted
N-acyl-anthranilic acids were obtained in
without K2S2O8, no desired product was observed. These results, moderate to high yields. We believed this new synthetic
coupled with the fact that the complex P1 can be easily methods with N, N-dimethyloxamic acid as carboxylate agent
generated at low temperature, suggest that the critical step of would stimulate chemists to advance other relevant catalytic
the reaction may actually involve a transient Pd (III) or Pd(IV) carboxylation processes.
intermediate (Scheme 2, condition D).24, 25 The reaction could
not proceed when using CO2 instead of N,N-dimethyloxamic
acid as the carboxylate agent, which may exclude the
possibility that the intermediate
A reacted with the CO2
released from N,N-dimethyloxamic acid during the reaction.
Scheme 2: Control experiments
We also carried out an intermolecular kinetic isotope effect
experiment by reacting N, N-dimethyloxoamic acid with
acetanilides or d5- acetanilides, respectively(Scheme 3). The
Scheme 4: A plausible reaction mechanism
(
kH/kD) value was determined to be 1.2, which proved that the
C-H bond cleavage of acetanilide is not involved in the rate-
determining steps of the reaction.
We thank the National Natural Science Foundation of China
(No. 21402243, 81522041, and 81373258), The Fundamental
Research Funds for the Central Universities (Sun Yat-sen
University) (No. 13ykpy09), Medical Scientific Research
Foundation of Guangdong Province (No. B2014105), the
National High-Tech R&D Program of China (863 Program)
(2012AA020307) for financial support.
Notes and references
a School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China,
E-mail:wyinuo3@mail.sysu.edu.cn and luohb77@mail.sysu.edu.cn; Fax: + 86-20-3994
3000
Scheme 3: Control experiments and the KIE studies
Base on the above experiments and previous literatures,7, 8,
† Electronic Supplementary Information (ESI) available: See DOI: 10.1039/c000000x/
1
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;
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