Palladium(II)/Lewis Acid-Catalyzed Oxidative Olefination/Annulation of N-Methoxybenzamides: Identifying the Active Intermediates through NMR Characterizations

Article abstract of DOI:10.1021/acs.joc.9b03484

Although Pd(II)-catalyzed C-H activation in arenes has been widely successful in organic synthesis with many palladacycle compounds isolated as the intermediates in ligand-directed C-H activation, direct identification of the reaction intermediates such as the π-complex prior to the C-H activation is still not successful because of their instability. In the present study, we introduce a Pd(II)/LA (LA: Lewis acid)-catalyzed oxidative olefination/annulation reaction between N-methoxybenzamides and acrylates with oxygen as the oxidant source, in which two intermediates, including an unsymmetrical η6-complex and a palladacycle species without the proton releasing to the environment, were identified through NMR characterizations. The in situ formation of the heterobimetallic Pd(II)/LA species such as Pd(II)/Sc(III) may have enhanced the electrophilic properties of the Pd2+ cation, thus improving the stability of the π-complex, herein, an unsymmetrical η6-complex, and improving its catalytic efficiency. The observed insensitive electronic effect preferred the concerted metalation-deprotonation (CMD) mechanism for this C-H activation, and the detected palladacycle intermediate without the proton releasing to the environment offered an experimental clue to support the proposed CMD mechanism.

Full text of DOI:10.1021/acs.joc.9b03484

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Article
Palladium(II)/Lewis Acid Catalyzed Oxidative Olefination/
Annulation of N-methoxybenzamides: Identifying the
Active Intermediates through NMR Characterizations
Jing-Wen Xue, Miao Zeng, Hongwu Jiang, Kaiwen Li, Zhuqi Chen, and Guochuan Yin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03484 • Publication Date (Web): 26 Jun 2020
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Palladium(II)/Lewis Acid Catalyzed Oxidative
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Olefination/Annulation
of
N-
methoxybenzamides: Identifying the Active
Intermediates through NMR Characterizations
Jing-Wen Xue, Miao Zeng, Hongwu Jiang, Kaiwen Li, Zhuqi Chen, and Guochuan Yin*
School of Chemistry and Chemical Engineering, Key laboratory of Material Chemistry for
Energy Conversion and Storage (Huazhong University of Science and Technology), Ministry of
Education, Hubei Key Laboratory of Material Chemistry and Service Failure, Huazhong
University of Science and Technology, Wuhan 430074, PR China.
OMe
CF3
O
N
O
O
OMe
O
Pd2+
H
Sc3+/Pd2+
OTf
OTf
O
N
OMe
Pd2+/Sc3+
H
Sc3+
N
H
R
O
O
R
R
CF3
a
(
)
unsymmetrical complex
Identified by NMR
OMe
N
CF3
Pd2+/Sc3+
:
CF3
O
O
O
O
OTf
OTf
Pd2+
O
O
OTf
OTf
OMe
N
Pd2+
Sc3+
Sc3+
Pd2+/Sc3+
HO
O
O
O
R
OTf
H
R
CF3
CF3
c
(
)
b
(
)
ABSTRACT: Although Pd(II)-catalyzed C-H activation in arenes has been widely successful in
organic synthesis with many palladacycle compounds isolated as the intermediates in ligand
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directed C-H activation, direct identification of the reaction intermediates such as π-complex
prior to the C-H activation is still not successful due to their instability. In the present study, we
introduce a Pd(II)/LA (LA: Lewis acid) catalyzed oxidative olefination/annulation reaction
between N-methoxybenzamides and acrylates with oxygen as the oxidant source, in which two
intermediates, including an unsymmetrical η6-complex and a palladacycle species without the
proton releasing to the environment were identified through NMR characterizations. The in-situ
formation of the heterobimetallic Pd(II)/LA species such as Pd(II)/Sc(III) may have enhanced the
electrophilic properties of the Pd2+ cation, thus improving the stability of the π-complex, herein,
an unsymmetrical η6-complex, and improving its catalytic efficiency. The observed insensitive
electronic effect preferred the concerted metalation-deprotonation (CMD) mechanism for this C-
H activation, and the detected palladacycle intermediate without the proton releasing to the
environment offered an experimental clue to support the proposed CMD mechanism.
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INTRODUCTION
Transition metal ions catalyzed activation and functionalization of the C-H bond in
(hetero)arenes is one of the most active topics in organic synthesis;1 among various redox metal
catalysts, palladium is the most popularly investigated one because of its high activity in
catalysis. Up to now, several mechanisms have been proposed for Pd(II)-catalyzed C-H
activation of (hetero)arenes, including electrophilic aromatic substitution (SEAr),2,3 concerted
metalation-deprotonation (CMD),4 Heck-like, oxidative C-H insertion and anionic cross-
coupling.5,6 In these mechanisms, SEAr and CMD mechanisms received the most support, in
which SEAr was convinced by the NMR identifications of the Wheland-type σ-complex and σ-π
continuum intermediates in C-H activation of electron-rich indoles,7 while CMD, characteristic
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of proton abstraction via a base-assisted agostic interaction, was proposed on the basis of
theoretical calculations for the C-H activation in arenes.8,9 Due to the low stability, the agostic C-
H complex with its plausible precursors such as π-complex was not directly identified yet.10
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Over the recent decade, ligand-directed C-H activation has attracted much attention in
organic synthesis.11-13 The ligand-anchoring apparently increased the opportunity of the C-H
activation by the metal ions, and improved the stability of the C-H bond activated intermediates,
that led to the isolation of a series of cyclometalation compounds.14-16 Even so, the experimental
identification of the Pd(II)-ligated arene intermediates, that is, the π-complex and/or the agostic
hydrogen complex, is still not successful in those ligand-directed C-H functionalization
reactions. Interestingly, there also have many arene-coordinated transition metal complexes that
were isolated with the X-ray crystal characterizations such as [Ru(p-cymene)Cl2]2 and various
metallocenes;17,18 however, these coordinated arenes generally did not proceed further C-H
activation and functionalization through the mechanisms described above. Even more, [Ru(p-
cymene)Cl2]2 could function as a catalyst to activate the C-H bond from exogenous arenes
through the CMD mechanism.19 We suspect that the direct observation of the Pd(II)-ligated arene
intermediate, that is, π-complex, may be accessible in Pd(II)-catalyzed C-H activation through
certain strategies to enhance the electrophilic properties of the Pd2+ cation, thus strengthening its
interaction with arene, but not harming its catalytic activity.
In investigating the reactivity of the active metal moieties with related Lewis acid (LA)
promoted catalytic oxidation by redox metal ions,20,21 we unexpectedly found that, in addition to
its redox properties, the Lewis acid properties of the Cu2+ cation may also play a significant role
in Pd(II)-catalyzed Wacker-type oxidations.22 As an evidence, the redox inactive Sc3+ can
accelerate Pd(II)-catalyzed olefin oxidation more efficiently than Cu2+ does, which inspired us to
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define the Pd(II)/LA catalyst strategy for organic synthesis. Currently, the Pd(II)/LA catalysis
has been successful in a list of synthetic reactions,23-27 and it has also been expanded to
Ni(II)/LA catalyzed oxidative S-P bond formation.28 In literature, directing group assisted
olefination/annulation has been convinced as an efficient protocol to synthesize isoindolinone
compounds.29 Herein, we present a Pd(II)/LA catalyzed oxidative olefination/annulation of N-
methoxybenzamides to synthesize isoindolinones, in which two reaction intermediates including
π-complex and cyclopalladation species without the proton releasing to the environment were
identified through NMR characterizations. Notably, this is the first experimental identification of
the π-complex in the Pd(II)-catalyzed C-H activation in arenes.
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RESULTS AND DISCUSSION
The investigation was initiated by using N-methoxylbenzamide 1a and butyl acrylate 2a as
the model substrates for the olefination/annulation reaction to optimize the reaction conditions.
In the presence of Pd(TFA)2 catalyst with oxygen as the oxidant source, the reaction of N-
methoxylbenzamide (1a) and butyl acrylate (2a) in HOAc at 100 °C gave the isoindolinone
derivative butyl (E)-2-(2-methoxy-3-oxoisoindolin-1-ylidene)acetate (3a) as the product in a low
yield (28%) (Table S1, entry 2). Gratifyingly, when Sc(OTf)3 was added to Pd(TFA)2 as the
catalyst, butyl 2-(2-methoxy-3-oxoisoindolin-1-yl)acetate (4a) was identified as an unexpectedly
product without 3a formation, and a 68% isolated yield of 4a was achieved (Table S1, entry 4).
In the control experiment, when Sc(OTf)3 alone was employed as the catalyst, neither 3a nor 4a
was detected as the product (Table S1, entry 16). Subsequently, a series of condition
optimizations including Pd(II) sources, Lewis acids, solvents, temperature and the time-course of
the reaction were investigated (see Table S1-S3 and Figure S1); it was found that
Pd(TFA)2/Sc(OTf)3 provided the best catalytic efficiency in the sealed tube with oxygen as the
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oxidant source in HOAc solvent at 100 °C. Therefore, the following investigations on the
substrate scope were based on Pd(TFA)2/Sc(OTf)3 catalyst.
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As shown in Scheme 1, Pd(TFA)2/Sc(OTf)3 can catalyze olefination/annulation of a list of
substituted N-methoxybenzamides with butyl acrylate 2a to give the compound 4 in the moderate
to good yields (4b-4q), and the reaction was insensitive to the electronic effects on the aromatic
ring of N-methoxybenzamides. With an electron-withdrawing group (NO2, F, Cl or Br) at the
meta or para position of the aromatic ring, it provided the product 4 in good yields (56-67%, 4b,
4c, 4e-4h); the electron-donating groups (Me, OMe or t-Bu) at the meta or para position also
gave 66%-75% yields of 4 (4j-4l and 4q), just slightly higher than those from electron-
withdrawing groups. Notably, no matter electron-withdrawing group or electron-donating group
bearing on the ortho position of the aromatic rings, it led to a low yield of 4 possibly due to the
steric effect. The substrate scope of this reaction can be extended to 3,4-dimethoxy substituted N-
methoxybenzamide, which gave 4m in 51% yield, and 3,5-difluoro and 3,5-dichloro substituted
N-methoxybenzamides gave 4n and 4o in 33% and 28% yields, respectively, while 3,4,5-
trifluoro-N-methoxybenzamide gave 4p in 24% yield. In addition, using 1-naphthamide as the
substrate gave 4r in 14% yield. 2a can also be replaced by methyl acrylate or ethyl acrylate,
which reacted with 1a to give the corresponding 4s and 4t in 66% and 70% yields, respectively.
Notably, the reaction between N-ethoxybenzamide and 2a provided only 39% yield of 4u, much
less than 68% yield of 4a, indicating that the electronic effect of the directing group also played a
significant role in this Pd(II)/Sc(III) catalyzed olefination/annulation reaction. Other heterocyclic
amides were also tested for this reaction; disappointingly, only thiophene reacting with 2a
provided the corresponding 4v in 24% yield. In addition, when the olefination/annulation
reaction of N-methoxylbenzamide 1a and butyl acrylate 2a was performed on a gram scale, 60%
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yield of product 4a was obtained under the optimized conditions. Anyway, adding Lewis acid to
Pd(TFA)2 can substantially improve its catalytic efficiency and change the product distribution in
this olefination/annulation reaction. In the case of without LA added, using Pd(TFA)2 alone as
the catalyst always provided 3 as the product in a low yield, thus highlighting the crucial role of
LA in this Pd(II)/LA catalyzed olefination/annulation reaction.
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Scheme 1 Substrate scope for the Pd(II)/Sc(III)-catalyzed olefinatin/annulation reaction.
O
O
O
O
Pd(TFA)2 10 mol%
Sc(OTf)3 20 mol%
Pd(TFA)2 10 mol%
AcOH, 100 o
O2 in sealed tube
OMe
OMe
R1
N
R1
R2
N OMe
N
R1
N
OMe
R2
R1
H
AcOH, 100 o
O2 in sealed tube
C
H
C
R2
R2
1
2
1
2
4
3
1
1
1
1
1
1
3a
3b
3c
3d
3e
, R =H, 28%
3f
4a
, R =H, 68%
, R =4-Cl, 13%
1
3l
4f
, R =4-OMe, 26%
1
, R =4-Cl, 59%
4l
, R =4-OMe, 75%
1
O
O
1
4b, R1=4-NO2, 63%
1
, R =4-NO2, trace
3g
3h
, R =3-Br, 10%
3m
, R =3,4-di-OMe, n.d.
4g
4h
, R =3-Br, 56%
4m
, R =3,4-di-OMe, 51%
R1
R1
N
OMe
N OMe
1
1
1
1
, R =4-F, 17%
1
, R =4-Br, 14%
1
3n
3o
3p
, R =3,5-di-F, n.d.
4c
4d
4e
, R =4-F, 67%
, R =4-Br, 60%
4n
4o
4p
4q
, R =3,5-di-F, 33%
1
1
1
1
, R =2-Cl, 12%
1
3i
3j
1
, R =2-Me, 16%
, R =3,5-di-Cl, n.d.
, R =2-Cl, 32%
4i
4j
, R =2-Me, 49%
, R =3,5-di-Cl,28%
BuO2C
BuO2C
1
1
1
, R =3-Cl, 14%
1
, R =3-Me, 13%
1
, R =3,4,5-tri-F, n.d.
1
, R =3-Cl, 64%
, R =3-Me, 67%
, R =3,4,5-tri-F, 24%
1
1
1
3k
1
, R =4-Me, 22%
3q
, R =4-t-Bu, 21%
4k
, R =4-Me, 71%
, R =4-t-Bu, 68%
O
O
O
O
O
O
N
OMe
N
OMe
N
OMe
N
OMe
N
OMe
N
OMe
EtO2C
EtO2C
BuO2C
3r
MeO2C
BuO2C
MeO2C
3t
4t
, 27%
O
, 70%
O
3s
4s
, 26%
O
, 66%
O
4r
, n.d.
, 14%
O
O
S
O
S
O
N
OMe
N
OMe
N
OMe
N
OEt
N
OMe
N
OEt
BuO2C
3v
BuO2C
3w
BuO2C
4v
BuO2C
3u
BuO2C
4w
BuO2C
, n.d.
, n.d.
, 24%
, 8%
, n.d.
4u
, 39%
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(TFA)2 (10 mol%), and Sc(OTf)3 (20 mol%)
with O2 in sealed tube in HOAc (2.0 mL), stirring at 100 °C for 12 h. Isolated yield.
Mechanistically, this olefination/annulation reaction should proceed through a C-C/C-N
bond formation process no matter 3a or 4a was generated as the final product. In order to clarify
the sequence of the reaction steps, several possible intermediates were synthesized to test the
following control experiments (Scheme 2). Firstly, when butyl (E)-3-(N-
methoxybenzamido)acrylate (5) was treated with Pd(TFA)2 alone in HOAc at 100 °C, the
formation of 3a was not observed in thin-layer-chromatography (TLC) analysis (Scheme 2,
eq.1). Secondly, 4a was also not obtained from butyl 3-(N-methoxybenzamido)propanoate (6) in
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the presence of Pd(TFA)2/Sc(OTf)3 catalyst (Scheme 2, eq.2). These two experiments clearly
disclosed that the C-N bond formation is not a prior step in the generation of 3a or 4a. Thirdly,
4a was tested as a substrate to address whether 3a was obtained through dehydrogenation of 4a;
however, the reaction did not proceed to generate 3a (Scheme 2, eq.3). Finally, butyl (E)-3-(2-
(methoxycarbamoyl)phenyl)acrylate (7), the olefination compound was tested as the substrate.
When Pd(TFA)2 alone was employed as the catalyst, 3a was obtained in 88% yield from 7,
whereas using Pd(TFA)2/Sc(OTf)3 or Sc(OTf)3 as catalyst, it provided 4a in 96% and 95%
yields, respectively, possibly through intramolecular aza-Michael addition (Scheme 2, eq.4).
Taken together, these control experiments clearly supported that the C-C bond formation through
oxidative olefination occurred prior to the C-N bond formation in the whole reaction; then,
Pd(II)/Sc(III) or Sc(III) itself catalyzed annulation of the intermediate 7 to achieve the final
product, 3a or 4a, respectively.
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Scheme 2 Control experiments for Pd(II)/Sc(III)-catalyzed olefination/annulation reaction.
O
O
OMe
Pd(II)
N
N
OMe
(1)
(2)
(3)
AcOH 2 mL
CO2Bu 100 oC/O2
BuO2C
5
3a,
N.R.
O
O
OMe
Pd(II)/Sc(III)
N
N
OMe
AcOH 2 mL
CO2Bu 100 oC/O2
BuO2C
6
4a,
N.R.
O
O
Pd(II)/Sc(III)
OMe
N
N
OMe
AcOH 2 mL
100 oC/O2
CO2Bu
BuO2C
4a
3a,
N.R.
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O
Pd(II)
N
OMe
5
6
7
O
BuO2C
OMe
AcOH 2 mL
100 oC/O2
N
H
(4)
3a
Yield 88%
O
8
9
CO2Bu
7
Pd(II)/Sc(III)
or Sc(III)
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N
OMe
BuO2C
4a
Yield 96%
Yield 95%
In reported Lewis acid-involved transition metal catalyzed organic synthesis,30-32 if a
substrate contains one carbonyl group, it was generally believed that LA was coordinated to the
carbonyl, which improved the catalytic efficiency in the consecutive reaction. In the present
study, a series of experiments was designed to address the similar role of LA in this Pd(II)/LA
catalysis. In the case of using N,4-dimethoxybenzamide (1l) as substrate, if Sc(OTf)3 was ligated
to the carbonyl group of 1l, two series of protons may be observed for 1l in its 1H NMR spectrum
when the ratio of Sc(OTf)3/1l was less than one. However, as shown in Figure S2, no matter the
ratio of Sc(OTf)3/1l was 1, 0.5 or 0.25, only one series of protons was observed with slightly
downshifted aromatic protons. Interestingly, the magnitude of the downshift was related to the
proportion of the Sc(OTf)3 loading, which may be attributed to the change of the solvent
properties due to the Sc(OTf)3 addition, but not conclusively. To further address the possibility
of the carbonyl group coordination on the Sc3+ cation, two more sets of control experiments were
designed by using N-benzyl-O-methylhydroxylamine (8) and N-(4-methoxybenzyl)-O-
methylhydroxylamine) (9) as the substrate which do not contain the carbonyl group. As shown in
1
Figure S3, both of them also displayed a similar downshift of protons in their H NMR spectra
upon adding Sc(OTf)3. Taken together, these 1H NMR experiments supported that the downshift
of protons in 1H NMR spectrum was not caused by the carbonyl group coordination of 1l on the
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Sc3+ cation, thus excluding it as a clue to indicate the interaction between Sc3+ and the carbonyl
5
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group of 1l.
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0.0010
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Pd(II)+Sc(III)/1l
Pd(II)/Sc(III)+1l
0.0009
0.0008
0.0007
0.0006
10
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60
70
80
90
Concentration of 1l (mM)
Figure 1 Correlation of substrate concentration with the kobs constant for the disappearance of
the characteristic peak of the catalyst when reacted with N,4-dimethoxybenzamide (1l).
To further address the role of the Sc3+ in this Pd(II)/Sc(III) catalysis, two parallel kinetic
experiments were conducted through UV-vis monitoring of the Pd(II) species decay at its
characteristic absorbance band, including 1) the reaction of 1l with the pre-mixed
Pd(TFA)2/Sc(OTf)3 in HOAc, and 2) the reaction of Pd(TFA)2 with the pre-mixed 1l/Sc(OTf)3 in
HOAc. As shown in Figure 1, the reaction rate between 1l and pre-mixed Pd(TFA)2/Sc(OTf)3
was faster than that of the reaction between Pd(TFA)2 and 1l/Sc(OTf)3, giving k2 values of 3.31 ×
10-9 M-1 s-1 and 1.95 × 10-9 M-1 s-1, respectively. Clearly, it is the interaction between Pd2+ and
Sc3+, rather than the interaction between 1l and Sc3+, which accelerated the C-H activation of 1l
by the Pd2+ cation. Additionally, in UV-vis characterization of the Pd(II)/Sc(III) catalyst, adding
Sc(OTf)3 to Pd(TFA)2 in HOAc solution revealed an obvious increase of its characteristic band
around 396 nm, which also indicated the formation of a new Pd(II) species (see Figure S7).26
Taken together, these experiments strongly supported that Sc3+ interacting with the Pd2+ cation,
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rather than coordinating to the carbonyl group of the substrate, accelerated this Pd(II)/Sc(III)
catalyzed olefination/annulation reaction.
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In our previous studies, the promotional effect of LA in Pd(II)/LA catalysis was attributed
to the formation of the heterobimetallic Pd(II)/LA species, which enhanced the electrophilic
properties of the Pd2+ cation, thus accelerating Pd(II)-catalyzed organic synthesis.22-27 In
addition, one heterobimetallic Ni(II)/Y(III) species was detected through the MS detections in
Ni(II)/Y(III) catalyzed oxidative S-P formation reaction, which was assigned as a diacetate
bridged Ni(II)/Y(III) species.28 Although the X-ray crystal structures of the Pd(II)/LA catalysts
were not obtained yet in those studies, various heterobimetallic Pd(II) species with acetate bridge
were widely reported with X-ray crystal characterizations in literatures.33-36 Notably, in
investigating the influence of the Pd(II) sources on this olefination/annulation reaction, it was
found that Pd(TFA)2/Sc(OTf)3 catalyst demonstrated a much better catalytic efficiency than
Pd(OAc)2/Sc(OTf)3 (68% vs 43% yield, entries 3 and 4, Table S1), even though HOAc was
employed as the solvent, indicating that the trifluoroacetate anion from Pd(TFA)2 was not
exchanged with the free OAc- anion in the solvent. In addition, using Pd(OTf)2 or
Pd(OTf)2/Sc(OTf)3 as catalyst also demonstrated a much poorer efficiency (21% and 37% yield,
respectively, entries 14 and 15, Table S1) than that of Pd(TFA)2/Sc(OTf)3 (68% yield, entry 4,
Table S1), indicating the OTf- anion exchange did not occur for Pd(TFA)2/Sc(OTf)3 to provide
Pd(OTf)3 as catalyst, and the OTf- bridged Pd(II)/Sc(III) species was also eliminated for this
catalysis. Taken these experimental data together with previous studies in this Pd(II)/LA
catalysis,22-28 a similar heterobimetallic Pd(II)/Sc(III) species having the trifluoroacetate bridge
may be in-situ generated in the solution and served as the active species for catalysis. In the
Pd(II)/Sc(III) structure, while the Sc3+ cation should have six ligands to form an octahedral
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structure, a few of its ligands such as OTf- anion or water may dissociate from Sc3+, thus a clean
octahedral structure of the Sc3+ cation was omitted in the coming discussion.
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Figure 2 1H NMR spectra of the interaction between catalyst and N,4-dimethoxybenzamide (1l)
in HOAc-d4 at 80 °C. The trifluoroacetate bridged Pd2+/Sc3+ structure is abbreviated as Pd2+/Sc3+
in the graph.
1
To elucidate the mechanistic details of this reaction, several H NMR studies on the semi-
reaction between N,4-dimethoxybenzamide (1l) and different catalysts in HOAc-d4 were
conducted, which were displayed in Figure 2. The 1H NMR spectrum of N,4-
dimethoxybenzamide (1l) in HOAc-d4 showed an AA’XX’ system peaks in the aromatic region
(δH = 7.81 and 6.99 ppm, Figure 2a), corresponding to the ortho- and meta-protons of the
aromatic ring in 1l. Next, two experiments were conducted by treating 1l with one equiv.
Pd(TFA)2 or Sc(OTf)3 at 80 °C for 10 min, respectively, prior to their 1H NMR detections. No C-
H bond activated intermediates/products were observed in either reaction (Figures 2b and 2c),
except that the chemical shifts of 1l slightly downshifted in the presence of Sc(OTf)3.
Remarkably, when 1l was treated with pre-mixed Pd(TFA)2/Sc(OTf)3 catalyst under 80 °C for 10
min, its 1H NMR signals changed completely, that is, the original proton peaks of 1l disappeared,
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meanwhile, three new proton peaks emerged with an integral ratio of 1:1:1, and exhibited as two
doublet peaks (δH = 7.27, 6.71 ppm, JH-H =8.4 Hz) with one singlet peak (δH = 6.34 ppm, Figure
2d). These new protons can be assigned to a new generated palladacycle compound as well as
those palladacycles in literatures.37,38 Clearly, the formation of the heterobimetallic Pd(II)/Sc(III)
species greatly improved the C-H activation capability of the Pd2+ cation, leading to the
formation of the palladacycle compound.
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To further trap the reaction intermediates prior to the palladacycle formation, a list of H
NMR kinetic experiments was conducted under different conditions. Firstly, 1H NMR kinetics of
the reaction between 1l and Pd(TFA)2 in HOAc-d4 at 80 °C for 180 min was conducted. In the
1H NMR monitored time-course of this reaction, many new peaks appeared while some of them
overlapped each other, and the final palladacycle compound was not as clean as that from
Pd(II)/Sc(III) catalyst (Figure S8). As a result, the confused spectrum made the reaction
intermediates unidentifiable. Similar phenomena may have frequently occurred in other Pd(II)-
catalyzed C-H bond activation of arenes, which blocks the chemists to identify the reaction
intermediates up to now.
1
Next, similar H NMR kinetics was examined for the semi-reaction of Pd(TFA)2/Sc(OTf)3
1
with 1 having different substituents. Gratifyingly, a clean, potentially resolvable H NMR
1
kinetics was observed in most cases (see Figures S9-S13), and two simplified H NMR kinetics
of using 1l and 4-bromo-N-methoxybenzamide (1h), respectively, as substrate were exampled
for the discussion about the reaction intermediate identifications (Figures 3 and 4). The 1H NMR
spectra of substrate 1l and 1h are shown in Figure 3a and Figure 4a, respectively; in Figure 3c
and Figure 4c, the chemical shifts of the final product can be assigned to the palladacycle
compounds 1l-c and 1h-c, respectively. In Figure 3b, the chemical shifts of aromatic protons in
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substrate 1l showed a slightly downshift when compared with those in Figure 3a (δH = 7.94 and
7.06 ppm vs δH = 7.81 and 6.99 ppm), in which the peak at δH = 7.06 ppm is overlapped with a
new small peak at δH = 7.07 ppm. Fortunately, in the case of 1h substrate (Figure 4b), this
overlap was avoided, and two cleanly separated peaks including δH = 7.73 and 7.68 ppm,
corresponding to a new generated small AA’XX’ system peak and the AA’BB’ system peak of
meta-proton on the aromatic ring of 1h, were observed. This new AA’XX’ system peak at δH =
7.73 ppm exhibited a 1:1 integral ratio to that of the AA’XX’ system peak at δH = 8.30 ppm,
while the AA’BB’ system peaks at δH = 7.8 and 7.68 ppm also exhibited an integral ratio of 1:1,
which can be assigned to the aromatic protons of 1h. In Figure 3b, since the integral area of the
peak at δH = 7.06 ppm combined with the overlapped small peak at δH = 7.07 ppm is equal to the
total integral areas of the peaks at δH = 7.94 and 8.41 ppm, it can be feasibly deduced that this
overlapped small peak at δH = 7.07 ppm exhibited an integral ratio of 1:1 to that at δH = 8.41
ppm. Thus, these two new peaks could be assigned to the aromatic protons of a new generated
reaction intermediate, abbreviated as 1l-a in Figure 3b and 1h-a in Figure 4b (see vide infra for
detailed structural assignments).
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Figure 3 H NMR spectra of the interaction between N,4-dimethoxybenzamide (1l, 0.02 mmol)
with pre-mixed Pd(TFA)2/Sc(OTf)3 catalyst (0.02 mmol/0.02 mmol) in HOAc-d4 (0.5 mL) at
room temperature. The trifluoroacetate bridged Pd2+/Sc3+ structure is abbreviated as Pd2+/Sc3+ in
the graph.
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Figure 4 H NMR spectra of the interaction between 4-bromo-N-methoxybenzamide (1h, 0.02
mmol) with pre-mixed Pd(TFA)2/Sc(OTf)3 catalyst (0.02 mmol/0.02 mmol) in HOAc-d4 (0.5
mL) at room temperature. The trifluoroacetate bridged Pd2+/Sc3+ structure is abbreviated as
Pd2+/Sc3+ in the graph.
In the aromatic area of 1H NMR spectra in Figure 3b and 4b, in addition to the substrate (1l
and 1h), palladacycle product (1l-c and 1h-c) with the assigned intermediate 1l-a and 1h-a, there
still exists another set of aromatic protons. In Figure 3b, analyzing the integral areas of the
aromatic protons of palladacycle compound 1l-c (δH = 7.27, 6.72 and 6.34 ppm) disclosed that
there should have a small peak completely overlapped with the aromatic meta-proton of 1l-c (δH
= 6.71 ppm), giving the apparent chemical shift at δH = 6.72 ppm. On the other side, the aromatic
protons at δH = 7.33 and 6.5 ppm demonstrated an integral ratio of 1:1 in Figure 3b. Notably, in
place of 1l with 1h as the substrate, the completely overlapped small peak at δH = 6.72 ppm in
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Figure 3b was clearly separated from the aromatic meta-proton of 1h-c at δH = 7.23 ppm
(doublet, JH-H=8.0 Hz), giving the chemical shift of 7.28 ppm (doublet), while the aromatic
proton at δH = 7.36 ppm in Figure 4b was partly overlapped with the aromatic meta-proton of 1h-
c, giving the chemical shift of 7.39 ppm. Notably, in Figure 4b, the integral areas of the aromatic
protons at δH = 7.28 and 7.15 ppm disclosed a ratio of 1:1. Taken together the 1:1 integral ratio
of the protons at δH = 7.33 and 6.5 ppm in Figure 3b, it can be deduced that these three aromatic
protons, that is, the chemical shifts at 7.39, 7.28 and 7.15 ppm in Figure 4b, exhibited an integral
ratio of 1:1:1, which can be assigned to another reaction intermediate, abbreviated as 1l-b in
Figure 3b and 1h-b in Figure 4b, respectively (see vide infra for detailed structural assignments).
Now, two reaction intermediates, a and b, prior to the final palladacycle c formation, have been
successfully identified in this semi-reaction based on the 1H NMR information from the aromatic
area in Figures 3 and 4.
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The chemical shifts of methoxyl groups in Figures 3b and 4b also indicated that two
reaction intermediates occurred prior to the palladacycle formation, and both of them
disappeared finally in Figures 3c and 4c. The confusing fact is that, their integral areas are almost
identical, and the similarly identical integral areas were also observed in the aromatic protons of
the intermediate a and b in both Figures 3b and 4b. Particularly, similar 1:1 integral ratio of a
and b intermediates was further observed in other para-substituted N-methoxybenzamides
(Figures S11 and S12), which blocks the assignment of the methoxyl groups to the intermediate
a and b in these semi-reactions. Fortunately, this phenomenon of 1:1 integral ratio was broken in
1
using 2,4-dichloro-N-methoxybenzamide as the substrate (Figure S13), in which the H NMR
signals for the aromatic and methoxyl protons of the intermediate a was still observed, whereas
those for b disappeared, thus excluding the tied 1:1 relationship of the intermediate a and b in
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this semi-reaction. Accordingly, the methoxyl group at low-field can be reasonably assigned to
the intermediate a, and the other at up-field is assigned to b in Figure 3b and 4b, respectively.
The 1:1 ratio of the intermediate a and b observed in different para-substituted N-
methoxybenzamide substrates can be attributed to that the C-H activation with this Pd(II)/Sc(III)
catalyst was insensitive to the substituent effect as shown in the studies on the substrate scope
(see Scheme 1). As a result, the change on the para-substituent did not affect the stability of the
intermediate a and b significantly, thus their 1:1 ratio was not broken in these semi-reactions.
However, the sharp change of the electronic effect on aromatic ring by using 2,4-dichloro-N-
methoxybenzamide as the substrate made a stability difference between a and b, resulting in the
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1
disappearance of b in H NMR detection, whereas a was still observed, thus breaking the 1:1
ratio of a and b.
Taken together, these NMR data clearly evidenced the occurrence of two reaction
intermediates, a and b, prior to the palladacycle formation in this Pd(II)/Sc(III) catalyzed
olefination/annulation reaction. For the intermediate 1h-a in Figure 4b, only two chemical shifts
at 8.30 and 7.73 ppm displayed as AA’XX’ system peaks, were disclosed for its aromatic
protons, indicating that its two protons on the ortho-positions of aromatic ring have the identical
chemical environment, and so do the two meta-protons. Therefore, it can be concluded that the
interaction of the Pd(II)/Sc(III) species with 1h to generate the intermediate 1h-a did not make a
difference in the chemical environment of its two ortho-protons, and so did for two meta-
protons. However, the chemical environment of aromatic protons in 1h-a did change when
compared with those in 1h, giving two chemical shifts at 8.30 and 7.73 ppm. On the other side,
the chemical shift of the methoxyl group in 1h-a downshifted to 4.35 ppm, indicating the
nitrogen atom of the amide group was ligated to the Pd2+ cation in the Pd(II)/Sc(III) species.
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Accordingly, an unsymmetrical η6-coordination of the Pd2+ cation on the aromatic ring could be
assigned to the chemical structure of the intermediate a as shown in Figures 4b and 5b. Due to
the unsymmetrical η6-coordination of the Pd2+ cation, it made two distal meta-protons on the
aromatic ring more electro-deficient, causing its significantly downshifted to 8.30 ppm, while
two ortho-protons slightly upshifted to 7.73 ppm due to the shielding effect of the Pd(II)/Sc(III)
species. Because of the identical chemical environment of two ortho-protons was not broken by
the unsymmetrical η6-coordination of the Pd2+ cation, they disclosed only one AA’XX’ system
peak in its 1H NMR spectrum, and so do the two meta-protons.
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For the intermediate b, comparing Figures 4b and 5b, it disclosed two doublet peaks at δH =
7.33 and 6.72 ppm, while another peak occurred at δH = 6.5 ppm which is plausibly singlet
(Figure 3b). Significantly, the integral areas of three peaks indicated a ratio of 1:1:1 as stated
above, and there was no other aromatic proton observed, clearly indicating that the intermediate
b had lost one aromatic proton, that is, the C-H bond in arene had been cleaved after
1
Pd(II)/Sc(III)-catalyzed C-H activation. Additionally, the H-13C HSQC spectrum disclosed that
the carbon linked to this singlet proton (δH = 6.5 ppm) is still in sp2 hybridization, not sp3
hybridization (Figure S14), thus confirming that the intermediate b is not a Wheland
intermediate. Furthermore, the pattern of three aromatic protons in the intermediate b is very
similar to that of the palladacycle compound c, except that their chemical shifts are slightly
downshifted, implying that the chemical environments of aromatic protons in b would be very
similar to those in the palladacycle product c. According to these clues, the chemical structure of
the intermediate b can be assigned as a palladacycle compound structurally similar to c but with
the cleaved proton, that is, H+, not released to the environment. One more unit of the positive
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charge on the intermediate b led to its aromatic protons slightly downshifted when compared
with the final palladacycle compound c.
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In literature, the CMD mechanism was popularly proposed for Pd(II)-catalyzed C-H
activation in arenes based on DFT calculations.8-10 In the present study, no Wheland complex
was observed, and the substituent effect was also not sensitive in the studies on substrate scope
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1
and H NMR kinetics. Particularly, in competitive olefination/annulation reaction using N,4-
dimethoxybenzamide (1l) and 4-fluoro-N-methoxybenzamide (1c) as the substrate mixtures
under the standard conditions, it provided an 1.08:1 ratio of 4l/4c as the product, and similar
1.04:1 ratio of 4k/4c was obtained by using N-methoxy-4-methylbenzamide (1k) and 4-fluoro-N-
methoxybenzamide (1c) as the substrate mixtures. Clearly, this Pd(II)/Sc(III) catalyzed
olefination/annulation reaction is insensitive to the substituent effect, leading to the conclusion
that the Wheland intermediate, that is, σ-complex, was not involved in this process, and the
CMD mechanism was preferred.
Scheme 3 The proposed C-H activation process and hetero-bimetallic Pd(II)/Sc(III) species.
OMe
CF3
O
N
O
O
OMe
O
Pd2+
H
Sc3+/Pd2+
OTf
OTf
O
N
OMe
Pd2+/Sc3+
H
Sc3+
N
H
R
O
O
R
R
CF3
a
(
)
unsymmetrical complex
OMe
N
CF3
Pd2+/Sc3+
:
CF3
O
O
O
O
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OTf
Pd2+
O
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N
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Sc3+
Sc3+
Pd2+/Sc3+
HO
O
O
O
R
OTf
H
R
CF3
CF3
c
(
)
b
(
)
As discussed early, in investigating the influence of the Pd(II) sources on the catalytic
efficiency, it was observed that using Pd(TFA)2 as the Pd(II) source demonstrated a much better
catalytic efficiency than Pd(OAc)2 did (68% vs 43% yield, entries 3 and 4, Table S1), even
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though HOAc was employed as the solvent. Clearly, trifluoroacetate served as the bridge in the
heterobimetallic Pd(II)/Sc(III) species, and it was not exchanged with the acetate anion from
solvent. Accordingly, the CMD mechanism through intramolecular proton abstraction via a base-
assisted agostic interaction was proposed for this Pd(II)/Sc(III) catalyzed C-H activation as
shown in Scheme 3. First of all, the N-methoxy amide group functioned as the directing group to
facilitate the formation of the unsymmetrical η6-complex, that is, the observed intermediate a.
Next, via an intramolecular agostic hydrogen abstraction by CMD mechanism, the intermediate
b was generated with the proton transferred to the ligated trifluoroacetate, thus the valence of
Pd2+ did not go to +4 charge by oxidative addition, and it still remained at the level of the +2
charge as well as those in other Pd(II)-catalyzed C-H activation by CMD mechanism.8,39
Releasing of the proton from b to the environment generated the final palladacycle c in this semi-
reaction. Compared with the intermediate c, the slightly downshifted aromatic protons of the
intermediate b in 1H NMR spectrum can be attributed to its one more unit of positively charged
state with H+. In addition, in view of that Pd(OAc)2/Sc(OTf)3 demonstrated a poorer catalytic
efficiency than Pd(TFA)2/Sc(OTf)3, the electrophilic properties of the Pd2+ cation in the
heterobimetallic Pd(II)/Sc(III) species played a more significant role than the base-assisted
intramolecular agostic hydrogen abstraction in catalysis.
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Although Pd(II)-catalyzed C-H activation of arenes have been extensively investigated in
the presence/absence of the directing group,13,40 the direct observation of the π-complex was not
reported yet, possibly due to its instability, even though such a π-complex was proposed as an
intermediate prior to the C-H activation in the CMD mechanism.10 Here, in the case of using
Pd(TFA)2 alone as the catalyst, the time-course of this semi-reaction monitored by 1H NMR also
1
disclosed a confused and unresolvable H NMR spectrum which blocked the assignments of
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protons to any plausible intermediate. Fortunately, using Pd(TFA)2/Sc(OTf)3 as the catalyst
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makes the H NMR kinetics of this semi-reaction becoming clean, and an unsymmetrical η6-
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complex could be successfully identified for the first time. The success of this assignment can be
attributed to the formation of the heterobimetallic Pd(II)/Sc(III) species which served as the
active species for C-H activation in this reaction. Binding a strong Lewis acid such as Sc3+ to the
Pd(II) species through trifluoroacetate bridge may have enhanced its electrophilic properties,
thus improving the stability of the η6-complex a, and making it 1H NMR distinguishable.
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Scheme 4 KIE experiments for Pd(II)/Sc(III)-catalyzed olefination/annulation reaction.
O
O
O
O
CO2Bu
2a
OMe
OMe
N
OMe
N
OMe
D4
N
N
(1)
D5
H
H
Pd(II)/AcOH
BuO2C
BuO2C
1a
3a-d4
3a
1a-d5
KIE=2.45
1a 1a-d
:
5=1:1
O
N
O
O
O
CO2Bu
2a
OMe
OMe
OMe
N
OMe
D4
N
N
D5
(2)
H
H
Pd(II)/Sc(III)
AcOH
CO2Bu
CO2Bu
4a-d4
4a
1a-d5
1a
KIE=2.45
1a 1a-d
:
5=1:1
To address whether the C-H activation is the rate determining step (rds) in this Pd(II)/Sc(III)
catalyzed olefination/annulation reaction, kinetic isotopic effect (KIE) experiments were
performed through competitive olefination/annualation reaction under the standard conditions
(For more details, see Supporting Information). As shown in Scheme 4, using Pd(TFA)2 alone as
the catalyst, the reactions of N-methoxylbenzamide 1a/1a-d5 with 2a provided 3a and 3a-d4 as
the product with a ratio of 2.45, indicating a KIE value of 2.45. Interestingly, in the case of using
Pd(TFA)2/Sc(OTf)3 as the catalyst which provided 4a and 4a-d4 as the products, the KIE value
was also 2.45, identical to that of using Pd(TFA)2, except that the products were different. This
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information not only supports that the C-H activation is the rds, and the coming
olefination/annulations are fast steps, but also may have implied that formation of the
heterobimetallic Pd(II)/Sc(III) species did not change the properties of the transition state in C-H
activation when compared with the C-H activation by the Pd(II) species alone, for example,
shifting from an early transition state to a late transition state, or vice versa.
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O
O
OMe
HOAc-d4
80 o
N
N
OMe
CO2Bu
C
Pd(II)/Sc(III)
MeO
MeO
CO2Bu
4l
(
)
2a
(
)
1l-c
(
)
1
Figure 5 H NMR kinetics of the semi-reaction between butyl acrylate (2a) and palladacycle
intermediate 1l-c with equivalent Sc(OTf)3 in HOAc-d4 at room temperature.
To further detect the reaction intermediate for this Pd(II)/Sc(III) catalyzed
1
olefination/annulation reaction, the H NMR kinetic experiments between the palladacycle 1l-c
and 2a were conducted. The reaction proceeded smoothly to give the final product 4l (Figure 5),
1
the H NMR kinetics clearly displayed the disappearance of two substrate with the formation of
4l; however, there was no reaction intermediate observed, even though several intermediates
such as the olefination intermediate 7 could be expected before 4l formation (see Scheme 2, eq.
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4). This 1H NMR kinetics is consistent well with the results from above KIE experiments, that is,
the activation of C-H bond in arene is the rds of the whole reaction, and the follow-up
olefination/annulation steps are fast.
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Scheme 5 A simplified mechanism for Pd(II)/Sc(III)-catalyzed olefination/annulation reaction.
O
OMe
N
R
Pd2+/Sc3+
H
O2
H
O
OMe
N
Pd(0)/Sc3+
R
R
O
Pd2+/Sc3+
OMe
I
N
H
O
N
OMe
CO2Bu
CO2Bu
Sc3+
R
III
Pd2+/Sc3+
CO2Bu
O
II
N
OMe
R
CO2Bu
IV
Taken together, a simplified catalytic cycle was proposed in Scheme 5 as well as those in
literatures.37,41-43 First, the N-methoxyl amide group directed C-H activation by the Pd(II)/Sc(III)
species led to the formation of the palladacycle compound I, and its detailed formation process
was described in Scheme 3. Next, olefin insertion of the compound I provided another
palladacycle compound II, which next generated the olefination product III through β-hydride
elimination with the Pd(0)/Sc(III) species formation. Finally, the intermediate III was catalyzed
by Sc3+ to provide the annulation product IV through aza-Michael addition, meanwhile the
Pd(0)/Sc(III) species was re-oxidized to the active Pd(II)/Sc(III) species by O2 to achieve the
catalytic cycle.
CONCLUSION
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In summary, a Pd(II)/LA-catalyzed olefination/annulation reaction was explored with
oxygen as the oxidant source, in which two reaction intermediates including an unsymmetrical
η6-complex and a palladacycle species without the proton releasing to the environment were
identified through NMR characterizations. Adding LA such as Sc(OTf)3 to the Pd(TFA)2 catalyst
significantly improved its catalytic efficiency and changed the product distribution. The
improved catalytic activity was attributed to the formation of the trifluoroacetate bridged
heterometallic Pd(II)/Sc(III) species, which enhanced the electrophilic properties of the Pd2+
cation, thus stabilizing the π-complex, herein, η6-complex, and making its identifiable through
NMR characterizations. The observed insensitive electronic effect in catalysis supported that a
CMD mechanism mediated this Pd(II)/Sc(III)-catalyzed olefination/annulation reaction, and the
identified palladacycle intermediate without the proton releasing to the environment also
provided a clue to support this mechanism. The intermediates identified in the present study may
benefit a better understanding of the fundamental knowledge about the Pd(II)-catalyzed C-H
activation in arenes.
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EXPERIMENTAL SECTION
1. Materials and Analytical Methods
Unless otherwise noted, all reagents were purchased from commercial suppliers and used
without further purification. Compounds 1a-1t was synthesized following the literature.29b
Compounds 8 and 9 were synthesized following the literature.44 Compounds 5, 6 and 7 were
synthesized following the literature with modifications.29b UV-vis spectra were collected on
Agilent Technologies Cary-8454 UV-vis spectrometer. The reactions were monitored by TLC
with Haiyang GF-254 silica gel plates (Qingdao Haiyang chemical industry Co. Ltd, Qingdao,
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China) using UV light or KMnO4 as visualizing agents as needed. Flash column chromatography
5
6
1
13
was performed using 200-300 mesh silica gel at increased pressure. H NMR spectra and C
7
8
9
1
NMR spectra for the synthesized compounds were recorded in CDCl3 or DMSO-d6 while H
NMR and 1H-13C HSQC spectra for kinetic analysis were recorded in HOAc-d4 on a Brüker AV-
400 spectrometer. Chemical shifts (δ) were expressed in ppm (parts per million) with TMS as the
internal standard, and coupling constants (J) were reported in hertz (Hz). High-resolution mass
spectra were obtained on mass spectrometer by using ESI FT-ICR Mass.
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2. General Procedure for Oxidative Olefination/Annulation of N-methoxybenzamides with
Pd(TFA)2/Sc(OTf)3 Catalyst in HOAc
In a typical procedure, Pd(TFA)2 (6.6 mg, 0.02 mmol) and Sc(OTf)3 (19.7 mg, 0.04 mmol)
were dissolved in HOAc (2 mL) in a glass tube. After pre-stirring the prepared solution for 20
min under 70 °C, 1 (0.2 mmol) and 2 (0.4 mmol) were added in. The glass tube was next sealed
under O2 atmosphere, and then stirred at 100 °C using IKA heating mantle for desired reaction
time. After the reaction, the solvent was removed under reduced pressure. The residual was
purified by column chromatography on a silica gel (Petroleum Ether/Ethyl Acetate: 1/1–3/1) to
give the corresponding products.
3. General Procedure for Oxidative Olefination/Annulation of N-methoxybenzamides with
butyl acrylate using Pd(II)/Sc(III) catalyst on a gram scale
In a typical procedure, Pd(TFA)2 (166.2 mg, 0.5 mmol) and Sc(OTf)3 (246.1 mg, 0.5 mmol)
were dissolved in HOAc (50 mL) in a round-bottom flask. After pre-stirring the prepared
solution for 20 min under 70 °C, 1a (755.8 mg, 5 mmol) and 2a (720 μL, 5 mmol) were added
in. The reaction flask was next sealed under O2 atmosphere, and then stirred at 100 °C using oil
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bath for 12 h. After the reaction, the solvent was removed under reduced pressure. The residual
was purified by column chromatography on a silica gel (Petroleum Ether/Ethyl Acetate: 3/1) to
give the corresponding products 4a (0.832 g, 60% yield).
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4. General Procedure for the Synthesis of butyl (E)-3-(N-methoxybenzamido)acrylate (5):
A mixture of N-methoxybenzamides 1a (75.6 mg, 0.5 mmol), butyl acrylate 2a (144 µL, 1
mmol), PdCl2(CH3CN)2 (25.6 mg, 0.1 mmol) and CuCl (54.6 mg, 0.11 mmol) in Et2O was
stirred for 8 h at 50 °C using oil bath in a high pressure reactor under O2 atmosphere. After that,
the solvent was removed by rotary evaporation. Finally, the residual was purified by column
chromatography on a silica gel (Petroleum Ether/Ethyl Acetate: 5/1 as the eluent) to give the
desired products 5 (31.9 mg, 23%).
5. General Procedure for the Synthesis of butyl 3-(N-methoxybenzamido)propanoate (6):
A mixture of N-methoxybenzamides 1a (75.6 mg, 0.5 mmol), butyl acrylate 2a (144 µL, 1
mmol) and t-BuOK (14.0 mg, 0.125 mmol) in MeOH was stirred overnight at room temperature.
After that, the solvent was removed by rotary evaporation. The residual was purified by column
chromatography on a silica gel (Petroleum Ether/Ethyl Acetate: 3/1 as the eluent) to give the
desired products 6 (81 mg, 58%).
6.
General
Procedure
for
the
Synthesis
of
Butyl
(E)-3-(2-
(methoxycarbamoyl)phenyl)acrylate (7):
Methyl anthranilate (1.51 g, 10 mmol) was dissolved in 10% NaOH aqueous solution and
stirred at 60 °C in a water bath overnight. The mixture was then acidified to pH=4 ~ 5 with 12 M
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HCl solution, and a white solid was precipitated, then filtered and dried in a vacuum oven to give
2-aminobenzoic acid as a white solid (1.32 g, 96% yield).
7
8
9
A solution of NaNO2 (552 mg, 8.0 mmol) in water (3 mL) was added dropwise to an ice-
cold 2-aminobenzoic acid (1.1 g, 8.0 mmol) in 42% HBF4 (3.3 mL). The mixture was stirring
continued for 1 h at 0 °C after which methanol (0.5 mL), butyl acrylate (1.6 mL, 11.2 mmol) and
Pd(OAc)2 (35 mg, 0.15 mmol) were added to the mixture, which was then heated to 60 °C in a
water bath for 1 h. Then the mixture was extracted with diethyl ether, and the extract was washed
with saturated aqueous NaHCO3, dried with Na2SO4 and concentrated by rotary evaporator. Then
the residue was purified by column chromatography on silica gel gave (E)-2-(3-butoxy-3-
oxoprop-1-en-1-yl)benzoic acid as a white solid (1.79 g, 90% yield).
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Subsequently, (E)-2-(3-butoxy-3-oxoprop-1-en-1-yl)benzoic acid (1.24 g, 5 mmol), SOCl2
(0.73 mL, 10 mmol) and pyridine (0.5 mL) in a CH2Cl2 (20 mL) solution was stirred at 40 °C in
a water bath for 4 h, then the butyl (E)-3-(2-(chlorocarbonyl)phenyl)acrylate containing mixture
was used for next step without further isolation after remove the solvent.
O-Methylhydroxylamine hydrochloride (0.42 g, 5 mmol) and K2CO3 (1.38 g, 10 mmol)
were dissolved in a mixture of H2O (15 mL) and EtOAc (30 mL) in a round bottom flask which
was cooled to 0 °C in an ice bath. Subsequently, butyl (E)-3-(2-(chlorocarbonyl)phenyl)acrylate
was added into above solution via syringe. Then the mixture was stirring at room temperature for
0.5 h. After that, the organic layer was washed with brine, dried with Na2SO4 and evaporated.
Finally, the residue was recrystallization from petroleum ether/ethyl acetate to give the desired
product 7 Butyl (E)-3-(2-(methoxycarbamoyl)phenyl)acrylate (0.83 g, 60% yield).
butyl (E)-2-(2-methoxy-3-oxoisoindolin-1-ylidene)acetate29a,29b (3a): White solid (Petroleum
1
Ether/Ethyl Acetate = 5/1, Rf = 0.58, 15.4 mg, 28% yield); H NMR (400 MHz, CDCl3) δ 9.01
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(d, J = 7.8 Hz, 1H), 7.85 (d, J = 7.3 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H),
6.00 (s, 1H), 4.24 (t, J = 6.6 Hz, 2H), 4.05 (s, 3H), 1.72 (dd, J = 9.2, 5.3 Hz, 2H), 1.46 (dd, J =
7
8
9
13
14.9, 7.4 Hz, 2H), 0.98 (t, J = 7.3 Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 166.1, 161.8,
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143.8, 133.7, 131.6, 130.3, 128.3, 127.5, 123.4, 97.9, 64.7, 64.5, 30.9, 19.3, 13.9.
butyl (E)-2-(6-fluoro-2-methoxy-3-oxoisoindolin-1-ylidene)acetate (3c): White solid (Petroleum
Ether/Ethyl Acetate = 5/1, Rf = 0.5, 10 mg, 17% yield); 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J
= 8.4 Hz, 1H), 7.82 (dd, J = 8.0, 5.2 Hz, 1H), 7.28 (dd, J = 8.4, 1.4 Hz, 1H), 6.00 (s, 1H), 4.22 (t,
J = 6.6 Hz, 2H), 4.02 (s, 3H), 1.74-1.65 (m, 2H), 1.44 (dq, J = 14.7, 7.3 Hz, 2H), 0.96 (t, J = 7.3
13
Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 167.4, 165.8, 164.8, 160.8, 142.9 (d, JC-F = 2.9
Hz), 132.4 (d, JC-F = 11.7 Hz), 125.4 (d, JC-F = 9.8 Hz), 123.4 (d, JC-F = 2.6 Hz), 119.0, 118.7,
116.3, 116.0, 98.7, 64.8, 64.5, 30.7, 19.2, 13.7; HRMS (ESI) m/z: calculated for C15H16FNO4
[M+H]+ : 294.1136, found: 294.1131.
butyl (E)-2-(4-chloro-2-methoxy-3-oxoisoindolin-1-ylidene)acetate (3d): White solid (Petroleum
Ether/Ethyl Acetate = 5/1, Rf = 0.68, 7.4 mg, 12% yield); 1H NMR (400 MHz, CDCl3) δ 9.01 (d,
J = 7.7 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.54 (d, J = 8.1 Hz, 1H), 6.02 (s, 1H), 4.23 (t, J = 6.7
Hz, 2H), 4.05 (s, 3H), 1.74-1.68 (m, 2H), 1.46 (dd, J = 15.0, 7.5 Hz, 2H), 0.98 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 165.8, 159.5, 142.1, 134.2, 133.2, 132.4, 131.5, 126.8,
123.4, 98.2, 64.7, 64.4, 30.7, 19.2, 13.7; HRMS (ESI) m/z: calculated for C15H16ClNO4 [M+H]+ :
310.0841, found: 310.0836.
butyl (E)-2-(5-chloro-2-methoxy-3-oxoisoindolin-1-ylidene)acetate (3e): White solid (Petroleum
Ether/Ethyl Acetate = 5/1, Rf = 0.7, 8.7 mg, 14% yield); 1H NMR (400 MHz, CDCl3) δ 8.98 (d, J
= 8.4 Hz, 1H), 7.81 (d, J = 1.5 Hz, 1H), 7.63 (dd, J = 8.4, 1.8 Hz, 1H), 6.01 (s, 1H), 4.24 (t, J =
6.7 Hz, 2H), 4.05 (s, 3H), 1.76-1.67 (m, 2H), 1.52-1.40 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H);
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13C{1H} NMR (101 MHz, CDCl3) δ 165.8, 160.4, 142.9, 138.0, 133.5, 129.7, 129.1, 128.3,
123.5, 98.5, 64.7, 64.5, 30.7, 19.2, 13.7; HRMS (ESI) m/z: calculated for C15H16ClNO4 [M+H]+ :
310.0841, found: 310.0836.
butyl (E)-2-(6-chloro-2-methoxy-3-oxoisoindolin-1-ylidene)acetate29b (3f): Yellowish solid
(Petroleum Ether/Ethyl Acetate = 5/1, Rf = 0.6, 8 mg, 13% yield); 1H NMR (400 MHz, CDCl3) δ
9.00 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 5.95 (s, 1H), 4.18 (t, J = 6.7 Hz,
2H), 3.97 (s, 3H), 1.69-1.61 (m, 2H), 1.39 (dq, J = 14.7, 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 165.7, 160.7, 142.6, 140.0, 131.7, 131.5, 128.5, 125.6,
124.4, 98.8, 64.8, 64.4, 30.8, 19.2, 13.7.
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butyl (E)-2-(5-bromo-2-methoxy-3-oxoisoindolin-1-ylidene)acetate (3g): White solid (Petroleum
Ether/Ethyl Acetate = 5/1, Rf = 0.75, 7 mg, 10% yield); 1H NMR (400 MHz, CDCl3) δ 8.93 (t, J
= 14.7 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.80 (dd, J = 8.4, 1.9 Hz, 1H), 6.03 (s, 1H), 4.23 (t, J =
6.7 Hz, 2H), 4.04 (s, 3H), 1.72 (dd, J = 9.7, 5.2 Hz, 2H), 1.46 (dq, J = 14.7, 7.4 Hz, 2H), 0.98 (t,
13
J = 7.4 Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 165.8, 160.3, 143.0, 136.4, 129.8, 129.1,
128.7, 126.5, 126.1, 98.6, 64.8, 64.5, 30.7, 19.2, 13.7; HRMS (ESI) m/z: calculated for
C15H16BrNO4 [M+H]+ : 354.0335, found: 354.0330.
butyl (E)-2-(6-bromo-2-methoxy-3-oxoisoindolin-1-ylidene)acetate29b (3h): White solid
(Petroleum Ether/Ethyl Acetate = 5/1, Rf = 0.7, 9.9 mg, 14% yield); 1H NMR (400 MHz, CDCl3)
δ 9.23 (d, J = 1.2 Hz, 1H), 7.78-7.69 (m, 2H), 6.02 (s, 1H), 4.25 (t, J = 6.7 Hz, 2H), 4.05 (s, 3H),
1.75-1.70 (m, 2H), 1.46 (dd, J = 15.1, 7.5 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 165.7, 160.9, 142.4, 134.7, 131.6, 131.3, 128.4, 126.1, 124.5, 98.9, 64.9, 64.5,
30.7, 19.2, 13.7.
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butyl (E)-2-(2-methoxy-4-methyl-3-oxoisoindolin-1-ylidene)acetate29b (3i): Yellowish solid
(Petroleum Ether/Ethyl Acetate = 5/1, Rf = 0.7, 9.2 mg, 16% yield); 1H NMR (400 MHz, CDCl3)
δ 8.79 (d, J = 7.8 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 5.87 (s, 1H), 4.15 (t,
J = 6.7 Hz, 2H), 3.95 (s, 3H), 2.63 (s, 3H), 1.68-1.58 (m, 2H), 1.46-1.31 (m, 2H), 0.90 (t, J = 7.4
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Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 166.1, 162.5, 143.7, 137.8, 133.9, 133.0, 130.7,
125.8, 124.2, 96.7, 64.5, 64.2, 30.8, 19.2, 17.5, 13.8.
butyl (E)-2-(2-methoxy-5-methyl-3-oxoisoindolin-1-ylidene)acetate29b (3j): White solid
1
(Petroleum Ether/Ethyl Acetate = 5/1, Rf = 0.71, 7.5 mg, 13% yield); H NMR (400 MHz,
CDCl3) δ 8.86 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 5.95 (s, 1H), 4.23 (t, J
= 6.7 Hz, 2H), 4.04 (s, 3H), 2.48 (s, 3H), 1.77-1.66 (m, 2H), 1.53-1.39 (m, 2H), 0.98 (t, J = 7.4
13
Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 166.1, 161.9, 143.9, 142.4, 134.2, 128.1, 127.6,
127.5, 123.7, 97.0, 64.5, 64.3, 30.8, 21.7, 19.2, 13.7.
butyl (E)-2-(2-methoxy-6-methyl-3-oxoisoindolin-1-ylidene)acetate29b (3k): Yellowish solid
1
(Petroleum Ether/Ethyl Acetate = 5/1, Rf = 0.5, 12.7 mg, 22% yield); H NMR (400 MHz,
CDCl3) δ 8.80 (s, 1H), 7.71 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 5.94 (s, 1H), 4.22 (t, J
= 6.7 Hz, 2H), 4.01 (s, 3H), 2.49 (s, 3H), 1.75 – 1.64 (m, 2H), 1.44 (dq, J = 14.7, 7.4 Hz, 2H),
0.96 (t, J = 7.3 Hz, 3H); C{1H} NMR (101 MHz, CDCl3) δ 166.1, 161.9, 144.6, 144.0, 132.2,
13
130.4, 128.7, 124.8, 123.2, 97.4, 64.6, 64.3, 30.8, 22.4, 19.2, 13.8.
butyl (E)-2-(2,6-dimethoxy-3-oxoisoindolin-1-ylidene)acetate29b (3l): White solid (Petroleum
1
Ether/Ethyl Acetate = 5/1, Rf = 0.48, 15.9 mg, 26% yield); H NMR (400 MHz, CDCl3) δ 8.66
(d, J = 1.8 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.07 (dd, J = 8.3, 2.0 Hz, 1H), 5.94 (s, 1H), 4.21 (t,
J = 6.7 Hz, 2H), 4.01 (s, 3H), 3.92 (s, 3H), 1.75-1.64 (m, 2H), 1.50-1.38 (m, 2H), 0.96 (t, J = 7.4
ACS Paragon Plus Environment
29