Pd(OAc)2-catalyzed one-pot preparation of anthranilates from acyclic unsaturated β-enamino esters

Article abstract of DOI:10.1016/j.tetlet.2020.151659

A one-pot synthesis of anthranilates from acyclic unsaturated β-enamino esters with a catalytic amount of Pd(OAc)₂ was achieved for the first time. The substrates for the key catalytic reaction were easily prepared from acetoacetate esters and amines, and functionalized anthranilates were obtained in moderate to good chemical yields. A simple assembly of a ¹³C-labeled anthranilate was demonstrated by applying this protocol. In addition, bioactive NNI-5 was synthesized using this catalytic process.

Full text of DOI:10.1016/j.tetlet.2020.151659

Journal Pre-proofs
Pd(OAc)2-catalyzed one-pot preparation of anthranilates from acyclic unsatu-
rated β-enamino esters
Shunya Mikami, Sho Okada, Ryo Kishimoto, Tetsuhiko Takabatake, Masahiro
Toyota
PII:
S0040-4039(20)30078-2
DOI:
https://doi.org/10.1016/j.tetlet.2020.151659
TETL 151659
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 December 2019
16 January 2020
21 January 2020
Please cite this article as: Mikami, S., Okada, S., Kishimoto, R., Takabatake, T., Toyota, M., Pd(OAc)2-catalyzed
one-pot preparation of anthranilates from acyclic unsaturated β-enamino esters, Tetrahedron Letters (2020), doi:
https://doi.org/10.1016/j.tetlet.2020.151659
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Pd(OAc)2-catalyzed one-pot preparation of
anthranilates from acyclic unsaturated
β-enamino esters
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Shunya Mikami, Sho Okada, Ryo Kishimoto, Tetsuhiko Takabatake, and Masahiro Toyota*

Tetrahedron Letters
Pd(OAc)2-catalyzed one-pot preparation of anthranilates from acyclic unsaturated
β-enamino esters
Shunya Mikami,a Sho Okada,a Ryo Kishimoto,a Tetsuhiko Takabatake,b and Masahiro Toyota*, a
aDepartment of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
b
Advanced Materials Development Laboratory, Sumitomo Chemical Co., Ltd., 1-98, Kasugadenaka, 3-chome, Konohana-ku, Osaka, 554-8558
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A one-pot synthesis of anthranilates from acyclic unsaturated β-enamino esters with a catalytic
amount of Pd(OAc)2 was achieved for the first time. The substrates for the key catalytic reaction
were easily prepared from acetoacetate esters and amines, and functionalized anthranilates were
obtained in moderate to good chemical yields. A simple assembly of a 13C-labeled anthranilate
was demonstrated by applying this protocol. In addition, bioactive NNI-5 was synthesized using
this catalytic process.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Anthranilates
β-enamino esters
Pd(OAc)2-catalyzed cyclization
13C-labeled anthranilate
Introduction
Some synthetic anthranilic acid derivatives exhibit divergent
biological activities. For instance, NNI-5 (1) shows antiviral
properties1 against the hepatitis C virus (HCV) which could have
a significant impact for the approximately 71 million people
living with chronic HCV infection.2 Another example of
biological activity is AAL993 (2), a vascular endothelial growth
factor (VEGF) kinase inhibitor, which shows potent
antiangiogenic and antitumor activities.3 Compound 3, which is a
new class of malonyl-CoA decarboxylase inhibitor, possesses
antiobesity and antidiabetic properties.4 Finally, compound 4, a
Staphylococcus aureus Sortase A inhibitor, is a promising
antibacterial agent5 (Figure 1).
Scheme 1. Cycloaromatization reactions.
The research on anthranilic acid (2-aminobenzoic acid) began
with its isolation from indigo by Fritzsche in 1841.6 Anthranilic
acid was industrially synthesized from phthalic anhydride,
available through oxidation of o-xylene via phthalamide.7 Most
substituted anthranilic acid derivatives have been prepared from
benzenoids, such as isatins8 and benzoic acids.9 Recently, a
myriad of different synthetic approaches to anthranilic acid
derivatives with or without transition metals10,11 have been
reported. To the best of our knowledge, only Ishikawa and Saito
have succeeded in a palladium-assisted anthranilate synthesis
using acyclic unsaturated β-enamino ester 5 (Scheme 1, eq-1).12
Figure 1. Structures of some bioactive anthranilic acid derivatives

4
5
6
7
8
Cu(OAc)2 (2)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (4)
Cu(OAc)2 (4)
none
DMSO
DMSO
toluene
DME
MeCN
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
45
45
45
45
45
45
60
120
60
60
60
60
60
10
75
9
As a variety of substrates suitable for this process (5 → 6) are
easily prepared from acetoacetate esters, this reaction could be
adaptable to a wide variety of substituted anthranilate syntheses.
However, there are still some challenges regarding its chemical
yield and catalyzation. We became interested in applying our
catalytic cycloaromatization protocol (7 → 8)13 shown in eq-2
(Scheme 1) to unsaturated β-enamino esters for the construction
of anthranilates.
10
36
62
76
55
83e
51
trace
0
9
10
11
12
13b
14
15c
16d
Results and Discussion
Cu(OAc)2 (4)
Cu(OAc)2 (4)
12
Our screening began with an effort to optimize the reaction
conditions for the one-pot synthesis of anthranilates using a
aThe reaction was run for 28 h. 5 mol % Pd(OAc)2. In the absence
of Pd(OAc)2. dUnder O2 (1 atm) atmosphere. e10 mol % PdCl2 (12%)
and Pd(TFA)2 (15%).
b
c
catalytic
amount
of
Pd(OAc)2.
Methyl
(E)-3-(pyrrolidin-1-yl)hepta-2,6-dienoate (9a) was chosen as a
model compound for the optimization process. The requisite
substrate 9a was synthesized using mono-alkylation of
acetoacetate-dianions14 and enamine formation.15 A variety of
different reaction parameters, such as the reoxidant, solvent, and
temperature were evaluated (Table 1). To begin, 9a was
subjected to our catalytic cycloaromatization conditions13 to
afford the desired anthranilate 10a in a 44% yield (Table 1, entry
1). There is no experimental evidence so far, however, in contrast
to hydrocarbons, whether nitrogen-containing compounds might
participate in palladium catalysts as
a
ligand or
nitrogen-containing substrates. It is also unknown whether their
intermediates may be further oxidized under an aerobic
atmosphere, and eventually those interactions could cause the
reduction of the chemical yields of anthranilates. Although
1,4-benzoquinone (BQ) did not work at all as a reoxidant (Table
1, entry 2), three equivalent CuCl2 functioned to a small degree
(Table 1, entry 3). When less than two equivalent Cu(OAc)2 was
used, 10a was obtained in about 10% yield (Table 1, entry 4).
However, three equivalent Cu(OAc)2 proved to be effective, and
10a was isolated in a 75% yield (Table 1, entry 5). Toluene,
1,2-dimthoxyethane (DME), and MeCN were unsuitable for this
catalytic process (Table 1, entries 6-8). It was found that DMF
can be used as an alternative solvent for DMSO (Table 1, entry
9). However, when the reaction was performed at 60 ˚C to clearly
produce 10a (Table 1, entry 10), the higher temperature (120 ˚C)
reduced the chemical yield. The reoxidation process in this
catalytic system did not proceed smoothly at 120 ˚C, most likely
due to the partial formation of palladium black, and eventually
the chemical yield was reduced to 55% (Table 1, entry 11). The
best yield (83%) was obtained using four equivalent Cu(OAc)2 as
a reoxidant (Table 1, entry 12). When the amount of catalyst was
lowered to 5 mol %, the yield also dropped to 51% (Table 1,
entry 13). The reaction hardly proceeded in the absence of the
reoxidant (Table 1, entry 14) or Pd(OAc)2 (Table 1, entry 15).
Although 9a disappeared by TLC-monitoring, no by-product was
isolated. It was found that the coexistence of oxygen and
Cu(OAc)2 not only cancelled each efficacy, but also somehow
caused uptake of the reaction substrate 9a (Table 1, entry 16).
Additionally, several other palladium catalysts, including PdCl2
(12%) and Pd(TFA)2 (15%), were also examined in this process,
but none proved to be better than Pd(OAc)2.
Table 1. Pd(OAc)2-catalyzed cyclization of unsaturated
β-enamino esters 9a.
PMB: p-methoxybenzyl; (a) DMSO (0.75 M), 45 ˚C. (b) 40 mol %
Pd(OAc)2, 3 equiv Cu(OAc)2. (c) 20 mol % Pd(OAc)2.
Scheme 2. Substrate scope.
The scope and limitations of this catalytic reaction were next
investigated using various unsaturated β-enamino esters 9b-o.
The results are summarized in Scheme 2.When ethyl
(E)-3-(pyrrolidin-1-yl)hepta-2,6-dienoate (9b) was used, the yield
fell to 62%. Even if the pyrrolidine ring portion of the reaction
substrate was changed to a piperidine ring or a morpholine ring,
the corresponding cyclized products 10c and 10d were obtained
entry
reoxidant (equiv)
solvent
temp (C)
isolated yield
(%)
44
0
1a
2
3
O2 (1 atm)
BQ (3)
CuCl2 (3)
DMSO
DMSO
DMSO
45
45
45
20

in the same manner, although there was a slight decrease in
yields. Methyl (E)-3-(4-methylpiperazin-1-yl)hepta-2,6-dienoate
(9e) and methyl (E)-3-(4-acetylpiperazin-1-yl)hepta-2,6-dienoate
(9f) gave rise to the corresponding cyclization products 10e and
10f in 68% and 75% yields, respectively. On the other hand,
methyl (Z)-3-(benzylamino)hepta-2,6-dienoate (9g) provided a
separable 2:1 mixture of 10g and 11g in 63% yield. Similarly,
ethyl (Z)-3-(benzylamino)hepta-2,6-dienoate (9h) and methyl
(Z)-3-((4-methoxybenzyl)amino)hepta-2,6-dienoate (9i) produced
a mixture of anthranilates 10h-i and N-benzylpyrrole derivatives
11h-i, respectively. Compounds 11g-i were obtained by
cyclization reactions of the allyl moiety and secondary amine part
of substrate 9g-i in a 5-exo-trig mode earlier than the usual
cycloaromatization reaction for 10g-i. To avoid the above side
reactions, methyl (Z)-3-(benzylamino)octa-2,7-dienoate (9j) was
prepared and subjected to this catalytic process. As expected, the
desired methyl 2-(benzylamino)-6-methylbenzoate (10j) was
obtained in 70% yield as the sole product. Compounds 10k and
10l were synthesized in good yields in the same manner. To
expand the versatility of this reaction, it was performed using
methyl (Z)-3-(phenethylamino)octa-2,7-dienoate (9m) and
methyl (Z)-3-(hexylamino)octa-2,7-dienoate (9n). As a result, it
was found that the desired products 10m-n were obtained in good
yields and the usefulness of this reaction was clarified. It has also
been confirmed that compound 6 can be obtained in a yield of
65% using this protocol. Although the detailed reason is not
clear, the catalytic cyclization of acyclic unsaturated β-enamino
esters having secondary amines tends to proceed smoothly
compared with the reaction substrates having tertiary amines,
most likely due to the reduced steric hindrance between the
amine moieties and ester groups. To investigate the
pharmacokinetics of biologically active anthranilic acid
derivatives, the synthesis of 13C-labeled anthranilates is essential.
Therefore, ethyl (E)-3-(pyrrolidin-1-yl)hepta-2,6-dienoate-3-13C
(9o) was synthesized and subjected to the reaction. To complete
the reaction in this case, 20 mol % of palladium acetate was
required and 10o was synthesized in 38% yield. It should be
noted that although there is room for yield improvement, it was
also possible to synthesize 10a directly from acetoacetate 12
using similar reaction conditions, and when this reaction was
carried out at a high concentration and high temperature, further
oxidized pyrrole 13 was obtained from 9a. (Scheme 3). When the
two conversion reactions shown in Scheme 3 were performed
using Cu(OAc)2 as a reoxidizing agent instead of oxygen, the
yield of 10a was reduced to 29%, and 13 was not obtained at all.
Compounds 10a and 13 were treated with Pd(OAc)2 and
Cu(OAc)2 in DMSO at 100 ° C and 120 ° C, respectively. As a
result, 10a and 13 were recovered intact. Although there is no
evidence to support the following speculation, in the one-pot
synthesis of 10a, pyrrolidine reacted with Cu(OAc)2 to dilute its
catalytic effect. On the other hand, under the higher concentration
and temperature, only the uptake of 9a by Cu(OAc)2 proceeded.
Further elucidation of the detailed reaction mechanism is
required.
Scheme 3. Some aspects of the catalytic reaction.
In order to clarify the reaction mechanism, the reaction was
quenched when the starting material 9a was still remaining. The
1H NMR of the crude product showed only the presence of 9a
and 10a, likely because the reaction intermediates were very
unstable. Although there is no evidence, the presumed reaction
mechanism is shown in Scheme 4. After activation of an isolated
olefin in 9a by Pd(OAc)2, an enamine in A attacks the terminal
carbon to generate the alkyl palladium intermediate B.
β-elimination of acetoxypalladium(II) hydride (D) produces
1,4-diene C, which was subsequently oxidized by Pd(OAc)2 to
furnish anthranilate 10a. Reductive elimination of AcOH from
intermediate D provides Pd(0) E, which was oxidized by
Cu(OAc)2 to create Pd(OAc)2. Although this reaction could be an
equilibrium process, this equilibrium reaction should be
terminated once the aromatic compound is formed, so only the
thermodynamically stable anthranilate 10a is formed.
Since compound 10i, convertible to bioactive NNI-5 (1), was
obtained through the present investigation, we embarked on the
synthesis of NNI-5 (1). Namely, DDQ oxidation of 10i led to
methyl 2-aminobenzoate,16 which was subjected to a Steglich
reaction17 with 1.5 equivalent 2-(4-chlorophenoxy)acetic acid
followed by hydrolysis to afford NNI-5 (1) in 30% yield, over
three steps (Scheme 5).
In conclusion, a wide array of acyclic unsaturated β-enamino
esters, easily prepared from unsaturated 3-keto esters and amines,
provided the corresponding anthranilates in moderate to good
chemical yields in the presence of catalytic amounts of
Pd(OAc)2. Commercially available ethyl 3-oxobutanoate-3-13C
was transformed to ethyl 2-(pyrrolidin-1-yl)benzoate-2-13C using
this catalytic process. Finally, the total synthesis of bioactive
NNI-5 was demonstrated by use of our synthetic substrate.
Scheme 4. Possible reaction mechanism.
Scheme 5. Synthesis of NNI-5 (1).
Dedication
Dedicated to the memory of Professor Hideo Nemoto
(1943-2018).
Declaration and Competing Interest

The authors declare no conflict of interest.
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▪ One-pot synthesis of anthranilates from
unsaturated β-enamino esters
▪ Novel approach to bioactive NNI-5
▪ Concise preparation of 13C-labeled anthranilate