Pd/C-catalyzed dehydrogenation of 2-cinnamoylbenzoic acids to 3-benzylidene-3H-isochroman-1,4-diones

Article abstract of DOI:10.1039/C8CC03402H

Pd/C, a widely accepted hydrogenation catalyst, is found to catalytically dehydrogenate 2-cinnamoylbenzoic acids to 3-benzylidene-3-H-isochroman-1,4-diones with H₂ as the only byproduct. This synthetic reaction proceeds without oxidants and hydrogen acceptors, thereby representing an atom- and step-efficient approach to a wide range of functionalized 3-benzylidene-3H-isochroman-1,4-diones.

Full text of DOI:10.1039/C8CC03402H

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Pd/C-Catalyzed Dehydrogenation of 2-Cinamoylbenzoic Acids to
3-Benzylidene-3H-isochroman-1,4-diones
Dejun Yang,ac Xuan Ji,a Jie Zhang,a Chenyang Zhang,a Mingfei Li,a Jin Li*b and Renhua Liu*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pd/C, a widely accepted hydrogenation catalyst, is found to
catalytically dehydrogenate 2-cinnamoylbenzoic acids to 3-
benzylidene-3-H-isochroman-1,4-diones with H2 as the only
byproduct. The synthetic reaction proceeds without oxidants and
hydrogen acceptors, thereby representing an atom- and step-
efficient approach to
a wide range of functionalized 3-
benzylidene-3H-isochroman-1,4-diones.
α,β-Unsaturated enones bearing α-oxygen substitution have
found numerous applications in pharmaceutical chemistry,
organic materials, polymer science, and asymmetric
hydrogenation. 3-Alkylidene-3H-isochromene-1,4-diones are
among the heterocyclic compounds containing α-oxygenated
α, β-unsaturated enone structural units. They are widely used
as raw material and synthetic intermediates in biological and
medical industry.1 For example, a number of quinonoid
compounds with antibiotic or antitumoral activity, such as
antipneumocystic agent atovaquone and 3-hydroxy-2-phenyl-
1,4-naphthoquinones, can be synthesized with 3-alkylidene-
Fig 1 Methods for the preparation of 3-alkylidene-3H-isochromene-1,4-diones
alkylidene-3H-isochromene-1,4-diones remains problematic
because the starting material 1,4-isochromandiones are not
readily available. Therefore, an additional synthetic sequence
for obtaining the raw material is required. In the existing
methods for synthesis of 1, 4-isochromandiones, the
bromination of 2-acetylbenzoic acid approaches exhibits
relatively high overall yields (Fig 1).3a,5 However, the
bromination approaches required the carbonyl α-C-H bond
prefunctionalization (bromination) prior to the coupling of the
carboxylic groups and the carbonyl α-methyl to form 1,4-
isochromandiones. These prefunctionalization processes
added the reaction step, and are problematic because of (i)
the need for stoichiometric hazardous brominative reagents
(e.g., molecular bromine) and lead to equimolar amounts of
byproducts; (ii) the challenge in curtailing overbromination to
di- or tri- substituted products and minimizing the O-
heterocyclic byproducts.
3H-isochromene-1,4-diones as raw material via
a
rearrangement procedure.2 Moreover, some 3-hydroxy-2-
phenyl-1,4-naphthoquinones can be further converted to
functionalized
and
potentially
biologically
relevant
indolonaphthoquinones and benzofuranonaphthoquinones by
an one-step reaction.3
In spite of the importance of this kind of heterocyclic
compound, existing approaches to 3-alkylidene-3H-
isochromene-1,4-diones are still rare. Current strategies for
the synthesis of 3-alkylidene-3H-isochromene-1,4-diones are
typically performed by condensation of 1,4-isochromandiones
with aldehydes.4 However, this condensation approach to 3-
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Table 1 Optimization of reaction conditionsa
O
O
Pd/C (10 mol % Pd)
Ar
Ar
O
OH
C2H5COOH,
N2, 130oC
O
O
1a-1q
2a-2q
Products (reaction, time, yield)
Isolated yield
(%)
O
O
O
O
Entry
Conditions
5 mol % Pd, C2H5COOH, 130 oC
7.5 mol % Pd, C2H5COOH, 130 oC
10 mol % Pd, C2H5COOH, 130 oC
12.5 mol % Pd, C2H5COOH, 130 oC
10 mol % Pd, C2H5COOH, 110 oC
10 mol % Pd, C2H5COOH, 120 oC
10 mol % Pd, C2H5COOH, 140 oC
10 mol % Pd, DMA, 120 oC
31
52
83
72
52
77
83
53
64
70
77
O
O
O
1
F
Cl
O
O
2
2a, 83%, 24h
2b, 87%, 22h
2c, 82%, 60h
3
O
O
O
4
O
O
O
CF3
OMe
5
O
O
O
6
2d, 75%, 36h
2e, 67%, 16h
2f, 63%, 28h
7
O
O
O
8
O
O
O
9
10 mol % Pd, DMA, 130 oC
O
O
O
10
11
10 mol % Pd, DMA, 140 oC
2g, 58%, 36h
2h, 60%, 38h
2i, 83%, 33h
10 mol % Pd, DMA, 150 oC
O
O
OMe
O
OMe
aReaction conditions: substrate 1a (0.25 mmol), Pd/C, solvent (1 mL), 1 atm
OMe
OMe
O
O
O
O
of N2.
O
OMe
O
From a point of view of directness of synthetic route, atomic
economy of reaction, and easy availability of starting material,
direct intramolecular dehydrogenative cyclization of 2-
cinnamoylbenzoic acids to 3-benzylidene-3H-isochroman-1,4-
diones with H2 release is the most straightforward strategy for
accessing this class of versatile compounds but difficult to
achieve. Herein we reported our results toward achieving the
reaction.
2j, 63%, 36h
2k, 64%, 36h
2l, 54%, 42h
O
O
O
OMe
O
O
O
O
S
OMe
O
OMe
O
O
2m, 73%, 20h
2n, 60%, 36h
2o, 93%, 12h
O
O
Pd/C is a commercially available catalyst widely used to
catalytic hydrogenation. However, recently we disclosed that
Pd/C has hydrogenation and dehydrogenation Janus-faced
catalysis. Our group has developed a class of Pd/C-catalyzed
oxidant- and hydrogen acceptor-free dehydrogenation
reactions where Pd/C dehydrogenates both C–H and X–H
bonds to C–X bonds, and alkanes to the alkenes with H2
release.6 We questioned whether it would be possible to
utilize Pd/C dehydrogenation activity to accomplish an
acceptorless dehydrogenation of 2-cinamoylbenzoic acids to 3-
alkylidene-3H-isochromene-1,4-diones.
O
O
O
O
2p, 66%, 24h
2q, 76%, 24h
Scheme 1 Scope of the dehydrogenative cyclization. Reaction conditions: substrate
(0.25 mmol), Pd/C(26.5 mg, 0.025 mmol Pd), C2H5COOH (1 mL), 130 oC, 1 atm of N2.
have also carboxylic groups, they seldom interfered with the
substrate carboxylic groups coupling with the double bonds.
Instead, carboxylic acid solvents provided high yields. We were
pleased to find that with a simple reaction condition of 10
mol% Pd, 1 atm of N2, and 130 °C without any additives, 83%
isolated yield was obtained.
With this idea in mind, we began to investigate the
feasibility of this dehydrogenation reaction with 2-
cinnamoylbenzoic acid as a representative substrate. The
initial experiment was carried out under selected conditions
(see Table 1, entry 8). To our delight, the reaction provided us
with 53% isolated yields, which clearly indicated our
hypothesis was feasible. Subsequently, a systematic condition
optimization was carried out, including reaction temperature,
solvent, acids, and use amount of the catalyst and the results
are exhibited in Table 1. As can be seen, strong polar aprotic
and acidic solvents are beneficial to the reaction. It is worth
mentioning that despite the fact that carboxylic acid solvents
With the optimized conditions in hand, we began to
examine the substrate scope of this new reaction. A variety of
2-cinnamoyl benzoic acid derivatives were synthesized for
examination of the applicability of the newly developed
dehydrogenation reaction. As can be seen in Scheme 1, a
broad range of various substituents, including electron-
donating and electron-withdrawing groups, were compatible
with this dehydrogenation reaction. Substrates with aryl,
naphthyl, heterocyclic aromatic, and anthracyl groups were
tolerated under the optimized conditions and gave substituted
3-benzylidene-3H-isochroman-1,4-diones in good to excellent
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D)6a-6c
. The HPdH active species can be converted to
O
O
O
O
palladium(0) and H2, and it can also reduce benzoquinone to
hydroquinone. To prove the generation of HPdH species in the
dehydrogenation process, we added benzoquinone in the
dehydrogenation of 2-cinamoylbenzoic acid to 3-benzylidene-
3H-isochroman-1,4-dione and allowed the reaction to carry
out under the optimized conditions. The experiment results
clearly showed that p-benzenediol generated, which
demonstrated the formation of HPdH active species indeed in
the dehydrogenation process.
Pd/C (10 mol % Pd)
C2H5COOH,
Ar
Ar
O
OH
N2, 130 o
C
(II)
(I)
D
H2
B
A
Pd
HPdH
C
To intuitively evaluate the potential of this dehydrogenation
reaction in synthesis of relevant compounds, we designed and
implemented a synthetic route for 3-hydroxy-2-phenyl-1,4-
naphthoquinones, in which the newly developed
dehydrogenation reaction was used as a key reaction step
(Scheme 3). Two naphthoquinone compounds were
synthesized with 2-acetylbenzoic acids as the starting material.
Compared with reported naphthoquinone synthesis that used
the same 2-acetylbenzoic acids as the starting material, our
dehydrogenation method shortened the synthetic route and
increased the overall yields, e.g. in the synthesis of 3-
benzylidene-3H-isochroman-1,4-dione, it afforded 75% overall
yields, but reported methods obtained 63% and 72% overall
yields, respectively (Fig 1). Moreover, our dehydrogenation
route eliminates the need for the prebromination of the
carbonyl α-C-H bonds prior to the cyclization step, being
intrinsically devoid of adverse consequences caused by the
bromination reaction step, which include wasteful use of
stoichiometric molecular bromine, reaction step adding,
overall reaction atom efficiency decreasing, and environment
pollutant generation.
O
PdH
O
H
Ar
Ar
PdH
O
O
O
O
(III)
(IV)
Scheme 3 Proposed Reaction Mechanism.
yields. Fluorine-containing substrates were suitable for the
dehydrogenative catalysis and afforded excellent yields (2b
,
2d). This may be of great interest in the synthesis of fluorine-
containing biologically relevant compounds. Generally, strong
coordinating sulfur-containing groups are prone to inactivation
of transition metal catalysts. But sulfur-containing substrate 1o
was submissive to the dehydrogenative catalysis and afforded
up to 93% isolated yields.
We depicted a probable mechanism for the reaction in
Scheme 2. This dehydrogenation process begins with the
oxidative addition of the O-H bond to palladium (0) (procedure
A), which produces organopalladium intermediate III. Then the
palladium-oxygen bond inserts itself in the double bond in a
syn addition to form IV intermediate. The intermediate IV is
converted to the desired products and concurrent formation
of HPdH by a syn beta-hydride elimination (procedure C). The
palladium (0) is regenerated by reductive elimination of H2,
which can be observed in our previous research (procedure
In conclusion, Pd/C is widely used in hydrogenation catalysis,
however, its potential in catalytic dehydrogenation remains
undeveloped. The results presented highlight the
dehydrogenation side of Pd/C, which makes the synthetic
route of 3-benzylidene-3H-isochroman-1,4-diones more
streamlined and greener. These dehydrogenative reactions
free of oxidants and hydrogen acceptors circumvent the
intrinsic oxidation complications, e.g. overoxidation, and also
avoid the byproducts from oxidants, and hydrogen acceptors.
The simple catalysis only using a recyclized catalyst exhibits
high isolated yields, functional-group tolerance, and atom
economy. These transformations achieve the synthetic goal
and at the same time produce H2(a clean energy carrier),
which may be of great interest in both synthetic chemistry and
energy chemistry.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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Scheme
2
Total Synthesis of 2-Hydroxy-3-phenyl-1,4-naphthoquinones via
Dehydrogenative Cyclization.
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