Copper/Palladium Bimetallic System for the Synthesis of Isobenzofuranones through [4 + 1] Annulation between Propiophenones and Benzoic Acids

Article abstract of DOI:10.1021/acs.orglett.0c03627

A copper/palladium-catalyzed annulation from benzoic acids and propiophenones for the synthesis of isobenzofuranones was reported. The Cu-(2,2,6,6-tetramethylpiperidin-1-yl)oxyl system showed a great ability to activate the C-H bond on the α- and β-carbons of a carbonyl group, and the in situ-generated enone intermediate in this reaction could be further transformed to construct isobenzofuranones with the catalysis of Pd(dba)2 (dba = dibenzylideneacetone). Various isobenzofuranones could be obtained in moderate to good yields, and a great atom economy was highlighted by utilizing this method.

Full text of DOI:10.1021/acs.orglett.0c03627

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Letter
Copper/Palladium Bimetallic System for the Synthesis of
Isobenzofuranones through [4 + 1] Annulation between
Propiophenones and Benzoic Acids
Xiao Liang, Mingteng Xiong, Heping Zhu, Keqiang Shi, Yifeng Zhou,* and Yuanjiang Pan*
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ABSTRACT: A copper/palladium-catalyzed annulation from
benzoic acids and propiophenones for the synthesis of
isobenzofuranones was reported. The Cu-(2,2,6,6-tetramethylpi-
peridin-1-yl)oxyl system showed a great ability to activate the C−H
bond on the α- and β-carbons of a carbonyl group, and the in situ-
generated enone intermediate in this reaction could be further
transformed to construct isobenzofuranones with the catalysis of
Pd(dba)2 (dba = dibenzylideneacetone). Various isobenzofur-
anones could be obtained in moderate to good yields, and a great atom economy was highlighted by utilizing this method.
sobenzofuranones were known to be highly important
diverse products.13 Recently, Baidya developed a green Ru-
Istructures in the fields of organic chemistry, natural catalyzed cross-coupling of carboxylic acids with olefins;
products, and medicinal chemistry.1 In recent years, more
notably, a carboxylic group worked as the directing group to
activate ortho-H to fulfill later intermolecular cyclization.14
Unfortunately, most of the above-mentioned methods suffered
and more literature has revealed its biological activities, such as
an antituberculosis agency,2 potential antinociceptive activity,3
from several shortcomings, for example, narrow scopes, special
requirement for expensive substrates or complicated catalysts,
low atom economy, and poor selectivity.
cytotoxic activity against a panel of three leukemia cancer cell
lines,4 and an antihypertensive/anti-inflammatory agency.5
Last year, the discovery of a novel West Nile Virus protease
inhibitor based on isobenzonafuranone was also reported.6
Traditionally, condensation between phthalaldehydic acids and
different acetophenones was used to synthesize isobenzofur-
anones, but the inaccessible starting materials may lead to
difficulties in broadening the scopes of substrates.7 Therefore,
in this way, it was imperative to develop a convenient and
efficient method.
Over the past few years, increasing novel methodologies for
constructing such structures have been reported.8 In 2017, Pan
and co-workers employed air to realize the oxidation of 2-
hydroxyacetophenones to form 2-keto aldehydes, which could
be further transformed to isobenzofuranones or quioxalines
with an acid or base catalyst.9 In 2018, Ackermann described
the Rh-catalyzed dehydrogenative alkenylation of benzoic acids
with different alkenes to obtain the corresponding isobenzo-
furanones under the assistance of electricity.10 In 2019, Shen
developed a 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ)/tert-butyl nitrite (TBN)-catalyzed direct oxidation of
a benzylic C−H bond, thus accomplishing an annulation of
several 2-benzylbenzoic acids.11 In 2019, Singh introduced the
ultraviolet flow oxidative reaction (UV-FOR) system to
achieve a synthesis of isobenzofuranones in just a very short
retention time.12 In 2018, Kapur reported the switchable Ru-
catalyzed C−H functionalization of benzoic acids with allyl
alcohols, during which, different metal additives could bring
According to our previous research, we once reported a Cu-
catalyzed synthesis of sulfonyl enaminones through the
oxidative cross-coupling of various sulfonamides and propio-
phenones via the key desaturation step.15 During this
transformation, with 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) and O2 as oxidants, enones and α, β-disubstituted
ketones were detected as the key intermediates. Inspired by the
analysis of the mechanism in the previous works, we surmised
that, whether we could take this strategy to bring the in situ-
generated enones to react with benzoic acids, the annulation
may be achieved through the lactonization process. Unfortu-
nately, in the early exploration, such transformation could not
be realized by using any kind of copper catalyst, so we turned
to think about introducing a second catalytic system to develop
a bimetallic system. In the latest years, various works involving
transition-metal-catalyzed C−H activation to fulfill the
intermolecular annulation were reported.16 Among this
literature, benzoic acid and benzamide derivatives were
Received: October 31, 2020
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© XXXX American Chemical Society
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a b
,
highlighted as the most common substrates to react with
different alkenes or alkynes, thus constructing corresponding
benzoheterocycle products. To finish the annulation, we did
believe that the activation of a C−H bond on the ortho carbon
atom of a carboxylic acid or amide was a key step to start the
transformation. In general, the carboxyl group can be seen as a
directing group to direct metal catalysts to functionalize a C−
H bond on its ortho position.17 Now that we have already
finished the desaturation of ketones, we may bring another
transition-metal salt, such as Pd, Rh, or Ir, into this reaction to
realize the combination of benzoic acids and in situ generated
enones. Apart from our previous work, we also investigated
various methods to achieve the desaturation of saturated
ketones for constructing the β-functionalization of ketones.18
Taken together, herein, we tried to develop a Cu−Pd
bimetallic system to realize the one-step synthesis of
isobenzofuranone by coupling saturated ketones and benzoic
acids.
Table 1. Optimization of the Reaction Conditions
c
entry
variations from the standard condition
none
yield (%)
1
72
nd
nd
55
25
49
48
nd
nd
56
35
57
62
64
52
2
without Cu
3
without Pd
4
5
6
7
8
9
10
11
12
13
14
15
Pd(OAc)2 instead of Pd(dba)2
(RhCp*Cl2)2 instead of Pd(dba)2
Cu(OAc)2 instead of CuF2·2H2O
CuTC instead of CuF2·2H2O
dimethyl sulfoxide instead of toluene
dimethylformamide instead of toluene
xylene instead of toluene
dichlorobenzene instead of toluene
TEMPO instead of 4-MeO-TEMPO
4-NHAc-TEMPO instead of 4-MeO-TEMPO
Ar atmosphere
To verify the feasibility of our design strategies (Scheme 1),
we utilized propiophenone 1a and o-methylbenzoic acid 2a as
O2 atmosphere
Scheme 1. Design Stategies
a
Reaction conditions: 1a (0.5 mmol), 2a (0.3 mmol), [Cu] (20 mol
%), [Pd] (5 mol %), oxidant (1 equiv), solvent (2 mL), stirred at 130
°C for 20 h. Isolated yields. nd indicates “not detected”.
b
c
the toluene derivatives were efficient (Table 1, entries 8−11),
such as toluene, xylene, and dichlorobenzene. Different
TEMPO derivatives were also tested; only 4-MeO-TEMPO
gave a better yield (Table 1, entries 12 and 13). Besides, when
some common organic and inorganic oxidants were invested
instead of TEMPO, such as K2S2O8, tert-butyl hydroperoxide
(TBHP), di-tert-butyl peroxide (DTBP), and Oxone, none of
them were suitable (see Table S1 for more screening
parameters in the Supporting Information). Finally, when
this reaction was implemented under an Ar or O2 atmosphere,
both led to the suppression of the yield (Table 1, entries 14
and 15).
When the optimal reaction conditions were determined, the
substrate scopes of propiophenone derivatives and benzoic
acid derivatives were explored to expand the substrate scope,
and all the results of various target compounds were
summarized in the volume of Scheme 2 and Scheme 3.
In general, either electron-donating (EDG) or electron-
withdrawing (EWG) groups on the ortho, meta, and para
positions of propiophenones were examined under the
standard conditions (Scheme 2). Most of the results were
good, especially for those substrates with alkyl groups (3b, 3c,
3k, 3m). As for the halo-groups, only the Cl-group and F-
group could be tolerated, while most of them presented
moderate to good yields (3d−3h). The Br-group and I-group
were not suitable for this system, and we speculated it was
possible that the C−Br or C−I bond was easily activated in the
existence of Pd(dba)2. In particular, those substrates with
strong EDG and EWG on the benzene ring could be converted
smoothly (3i and 3j), while a substrate bearing a nitro group
only produced a trace yield (less than 10%). Notably, the
substrates with aryl groups could afford the corresponding
isobenzofuranones in good yields (3l, 3q, and 3r), and even
the bulky heterocycle group showed an acceptable reactivity
(3s and 3t). Furthermore, several electron-donating hetero-
cycle-containing compounds, such as 2-propionythiophene and
2-propionyfuran (3o and 3p), were both appropriate for this
the standard starting materials. When different conditions were
changed to investigate the yield of target product 3a, the best
result showed that 3a could be separated in 72% isolated yield,
and the optimal parameters were finally determined, which
were listed as follows: propiophenone (1a, 0.5 mmol), o-
methylbenzoic acid (2a, 0.3 mmol), CuF2·2H2O (20 mol %),
Pd(dba)2 (5 mol %) (dba = dibenzylideneacetone), 4-MeO-
TEMPO (1 equiv), toluene (2 mL) as the solvent. Last, this
reaction was implemented in the sealed Schlenk tube, which
was full of air atmosphere, at 130 °C for 20 h. In the early
trials, we preferred to concentrate on the choices of different
metal salts. Pd and Rh species were appropriate for this system,
but Pd(dba)2 gave a higher yield. (Table 1, entries 4 and 5).
According to the results, Cu(I) and Cu(II) species both could
be used as the catalysts (Table 1, entries 6 and 7), which
suggested it was possible that this reaction involved a single
electron transfer (SET) process and that the copper salts
helped to trigger this catalysis. However, the target products
cannot be examined in the absence of copper salts or palladium
salts (Table 1, entries 1 and 2), which may refer to the reaction
being a bimetallic cocatalysis process. As for the solvents, only
B
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a b c
, ,
a b
,
Scheme 2. Substrate Scope of Ketone Derivatives
Scheme 3. Substrate Scope of Benzoic Acid Derivatives
a
Reaction conditions: 1 (0.5 mmol), 2a (0.3 mmol), CuF2·2H2O (20
mol %), Pd(dba)2 (5 mol %), 4-MeO-TEMPO (1 equiv), toluene (2
mL), stirred at 130 °C for 20 h. 1 (0.5 mmol), 2a (0.3 mmol),
Cu(OAc)2 (20 mol %), Pd(dba)2 (5 mol %), 4-NHAc-TEMPO (1
b
a
Reaction conditions: 1a (0.5 mmol), 2 (0.3 mmol), CuF2·2H2O (20
mol %), Pd(dba)2 (5 mol %), 4-MeO-TEMPO (1 equiv), toluene (2
mL), stirred at 130 °C for 20 h. Isolated yields.
c
b
equiv), toluene (2 mL), stirred at 120 °C for 20 h. Isolated yields.
system, whereas 2-propionypyridine cannot be transformed to
its product. However, aliphatic ketones and propionamides did
not work under this system.
(Scheme 4, entry 2). Furthermore, H/D exchange experiments
were conducted to confirm the existence of C−H activation
triggered by palladium salts in this catalysis. Without copper
salts, ∼18% of the ortho-H could be exchanged under the
standard condition (Scheme 4, entry 3a). Dramatically, when
the TEMPO species was removed from this reaction, only 2%
of the ortho-D could be detected (Scheme 4, entry 3b). In this
way, it informed us that TEMPO, acting as an assistant, helped
the palladium salts to accomplish that activation. Then, when
an α,β-unsaturated ketone attended this reaction to react with
2a, the target compound could be isolated in 58% yield,
illustrating that such an enone compound was the key
intermediate product formed in the transformation (Scheme
4, entry 4). To explore more, we paid more attention to collect
the kinetic data of the reaction, especially for the kinetic
isotope effect (KIE, Scheme 4, entries 5 and 6). According to
results shown before, an α,β-unsaturated ketone was utilized as
the starting material to react with benzoic acid to test the KIE
data. A competitive KIE was determined by checking the
coupling of an α,β-unsaturated ketone with an equimolar
mixture of benzoic acid and deuterated benzoic acid for 90
min. After the mixture of products was collected, the value of
KIE was determined at 3.0 by means of NMR. Furthermore,
the parallel KIE value observed in parallel reactions from 30 to
75 min, at 2.7, suggested that the activation of a C−H bond on
the ortho position of a carboxylic group was confirmed as the
rate-limiting step of the Pd cycle. Finally, we tried to increase
More benzoic acids were checked to test the further
applicability of this bimetallic cocatalysis system. As shown
in Scheme 3, to our delight, the substrates with different alkyl
groups, such as methyl, ethyl, propyl, butyl, and cyclohexyl, on
the different positions of the benzene ring exhibited a good
compatibility with the reaction (4b−4h). Surprisingly, the
halo-substituents suppressed the transformation so much, only
4i could be separated in low yield. The acids with electron-
donating substituents, such as methoxyl (4k) and ethoxyl (4l)
groups, gave a moderate yield, while those with strong
−
−
electron-withdrawing substituents, such as NO2 and CF3 ,
showed no reactivity. Additionally, steric hindrance consid-
erably influenced the result; only 28% yield could be obtained
(4j). In addition, disubstituted (4m−4o) substrates could
afford the corresponding enaminones in moderate yields.
Unfortunately, acrylic acid, phenylacetic acid, and benzamide
cannot be transformed to corresponding target compounds.
Various control experiments were designed to disclose a
more accurate mechanism of the reaction (Scheme 4).
According to the results, Pd species, Cu species, and
TEMPO species were all the key factors for this reaction, so
all of them cannot be replaced (Scheme 4, entries 1a−1c).
Next, substrate 1a was easily transformed to the α-TEMPO
substituted propiophenone with the catalysis of copper salts,
which was consistent with the results of our previous research
C
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Scheme 4. Control Experiments
Scheme 5. Proposed Mechanism
protocol proposed here showed amounts of advantages just
like convenient starting substrates, very high selectivity, broad
substate scope, and great atom economy. Further studies
aiming at broadening the reaction scope for more inactivated
ketones and realizing the asymmetric transformation for
isobenzofuranones are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03627.
this reaction up to 10 times scale; corresponding products
could be obtained with a lower but acceptable conversion
(Scheme 4, entry 7), which showed potential applications in
the industry.
Experimental procedures, characterization data, NMR
spectra (PDF)
On the basis of the results of control experiments and
reported works, a possible mechanism was proposed in
Scheme 5. On the one side, the organometallic complex A
formed and subsequently transformed into the important
radical species B, which could be easily captured by another
TEMPO to generate C, followed by the elimination process to
release the enone D. On the other side, oxidative addition
afforded intermediate E, as a process of C−H activation. Next,
the insertion of the enone D would then give metal complex F.
Though it may in fact go through a reductive elimination to
form a six-membered ring product, no signals of such a product
could be detected by NMR. Therefore, in this way, it was
reasonable to presume β-hydride elimination took place to give
the palladium hydride species G. Undergoing another
insertion, a key six-membered ring Pd-cycle H was generated,
while with subsequent reductive elimination, it was finally
successfully transformed to the target molecule.
To sum up, herein, we reported a versatile method to
synthesize isobenzofuranones by using a Cu−Pd bimetallic
system through [4 + 1] annulation between propiophenones
and benzoic acids in moderate to good yields. Our research
could provide a special way to achieve the difunctionalization
of a β-carbon atom of the carbonyl group in saturated ketones
and reveal the possible potential to accomplish intermolecular
annulation through this bimetallic cocatalysis strategy. The
AUTHOR INFORMATION
Corresponding Authors
■
Yifeng Zhou − College of Life Sciences, China Jiliang
University, Hangzhou 310018, Zhejiang, P. R. China;
Email: panyuanjiang@zju.edu.cn
Yuanjiang Pan − Department of Chemistry, Zhejiang
University, Hangzhou 310027, Zhejiang, P. R. China;
orcid.org/0000-0003-2900-2600; Email: zhouyifeng@
cjlu.edu.cn
Authors
Xiao Liang − Department of Chemistry, Zhejiang University,
Hangzhou 310027, Zhejiang, P. R. China
Mingteng Xiong − Department of Chemistry, Zhejiang
University, Hangzhou 310027, Zhejiang, P. R. China
Heping Zhu − Department of Chemistry, Zhejiang University,
Hangzhou 310027, Zhejiang, P. R. China
Keqiang Shi − Department of Chemistry, Zhejiang University,
Hangzhou 310027, Zhejiang, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03627
Notes
The authors declare no competing financial interest.
D
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́
Silva, I. E. P.; Mendes, T. A. d. O.; da Silva, A. M.; Dias, R. S.; da Silva,
ACKNOWLEDGMENTS
■
̂
C. C.; Poleto, M. D.; Teixeira, R. R.; de Paula, S. O. Discovery of
This work was supported by the National Natural Science
Foundation of China (No. 21532005) and the National Key
R&D Program of China (No. 2016YFF0200503).
Novel West Nile Virus Protease Inhibitor Based on Isobenzonafur-
anone and Triazolic Derivatives of Eugenol and Indan-1,3-dione
Scaffolds. PLoS One 2019, 14, No. e0223017.
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