Highly-functionalized arene synthesis based on palladium on carbon-catalyzed aqueous dehydrogenation of cyclohexadienes and cyclohexenes

Article abstract of DOI:10.1039/c7gc03819d

Transition metal-catalyzed dehydrogenation is a clean oxidation method requiring no additional oxidants. We have accomplished a heterogeneous Pd/C-catalyzed aqueous dehydrogenation of 1,4-cyclohexadienes and cyclohexenes to give the corresponding highly-functionalized arenes. Furthermore, various arenes could be efficiently constructed in a one-pot manner via a Diels-Alder reaction and the following dehydrogenation.

Full text of DOI:10.1039/c7gc03819d

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Highly-Functionalized Arene Synthesis Based on Palladium on
Carbon-Catalyzed Aqueous Dehydrogenation of Cyclohexadienes
and Cyclohexenes
Received 00th January 20xx,
Accepted 00th January 20xx
Naoki Yasukawa, Hiroki Yokoyama, Masahiro Masuda, Yasunari Monguchi, Hironao Sajiki* and
Yoshinari Sawama*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The transition metal-catalyzed dehydrogenation is
oxidation method requiring no additional oxidant. We have required very high temperature (over 220 oC) under neat
accomplished heterogeneous Pd/C-catalyzed aqueous conditions and the yields and purities of products were not so
dehydrogenation of 1,4-cyclohexadienes and cyclohexenes to give high, Pd/C-catalyzed dehydrogenation of cyclohexene
a clean applicability was not investigated. Although the reaction
a
a
the corresponding highly-functionalized arenes. Furthermore, the derivatives was also recently reported.7 Because H2O plays an
various arenes could be efficiently constructed in a one-pot important role to suppress the ignition of Pd/C, the
manner via Diels-Alder reaction and the following development of the dehydrogenation method proceeding in
dehydrogenation.
H2O as a green solvent is highly desired. Herein, we report the
oxidant-free Pd/C-catalyzed dehydrogenation of 1,4-
Highly-functionalized arenes are useful building blocks to
construct various functional materials, such as plastics,
electronic devices, pharmaceutical agents, etc.1 Unsaturated
cyclohexadienes (3) and cyclohexenes (3’) in the presence of
acrylic acid derivatives as effective H2 acceptors in H2O to
produce various highly-functionalized arenes, such as biaryl,
heterobiaryl, and terphenyl derivatives (Scheme 1).
Additionally, the one-pot arene synthesis via Diels-Alder
reaction between 1,3-dienes and dienophiles and the following
Pd/C-catalyzed dehydrogenation were also effectively
alicyclic hydrocarbon derivatives [1,4-cyclohexadiene (3) and
cyclohexene derivatives (3’), which are easily prepared by
Diels-Alder reaction ([4+2] cycloaddition) between 1,3-dienes
(
1) and alkynes (
2)/alkene (2’)] are frequently utilized as
starting materials to be transformed into arenes (
4
) by the use
accomplished.
R2
of stoichiometric oxidants, such as 2,3-dichloro-5,6-dicyano-p-
benzoquinone (DDQ)2 and Mn oxides3 in organic solvents. The
homogeneous Pd-catalyzed oxygen oxidation of cyclohexenes
into arene derivatives has been reported as a clean oxidation
method.4 Meanwhile, the dehydrogenation of organic
compounds5 (e.g., alcohols,5a-e hydrocarbons5a,
R2
R2
H2
R3
2'
R3
R3
Pd/C
H2O
2
or
ꢀ
+ High atom economy
R1
R1
3
R1
Diels-Alder
reaction
+ Broad scope of substrates
+ Environmentally friend
+ One-pot synthesis from 1
1
3'
4
or
5b, 5f,
5g) has
Scheme
cyclohexenes.
1
.
Dehydrogenative aromatization via cyclohexadienes and
attracted attention as an oxidant-free oxidative method
accompanied by the emission of hydrogen gas (H2). The
dehydrogenation of N-heterocycles and tetrahydrophthalenes
using photo-redox catalysts into heteroarenes and
naphthalenes was recently reported,5f however, the
efficiencies of the dehydrogenation of cyclohexene derivatives
are desired to be improved. Although the Pd/C-catalyzed
dehydrogenation of dimethyl 3,6-diphenylcyclohexa-1,4-diene-
1,2-dicarboxylate into terphenyl in toluene was utilized for the
synthesis of (2,1-α)-indenofluorene derivatives,6 the substrate
We have initially optimized the reaction conditions of the
aqueous dehydrogenative aromatization of 1,4-cyclohexadiene
derivative (3a) prepared by Diels-Alder reaction of 1-phenyl-
1,3-butadiene and dimethyl acetylenedicarboxylate (Table 1).
Although 3a (0.1 mmol) was transformed into the desirable
biaryl product (4a) in 70% by the 10% Pd/C (5 mol%)-catalyzed
o
dehydrogenation in H2O at 120 C for 6 h, the corresponding
cyclohexane derivative (5a) was obtained in 27% as a by-
product in the Pd/C-catalyzed hydrogenation of 3a due to in
situ-generated H2 (entry 1). While the addition of 10 equiv. of
olefin derivatives (e.g., 1-hexene, vinyl acetate, sodium
acrylate) as the H2-acceptor significantly improved the yield of
4a (entries 2-4), acrylic acid or methyl acrylate was found to be
the best H2-acceptor to give 4a in quantitative yield (entries 5
and 6). The reduction in the amount (5 equiv.) of acrylic acid
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was still effective (entry 7), and a further decrease of acrylic
acid up to 3 equiv. caused the formation of the undesired 5a
(entry 9). The dehydrogenation of 3a could effectively proceed
o
even at 80 C to give 4a in quantitative yield, while a further
o
lower temperature (60 C) gave a disappointing result (entries
9 vs. 7 and 10). [Further detailed optimization analyses are
described in Tables S1 and S2 (ESI)]. The fifty-fold scale-up
reaction of 3a (5 mmol) could be successfully performed to
give 4a in 95% yield (entry 11). During the present
dehydrogenation, no Pd leaching was detected by an
Inductively Coupled Plasma-Optical Emission Spectrometry
(ICP-OES) analysis (See Table S4 in the ESI).
Table 1. Optimization of the reaction conditions.a
entry additive (x equiv.)
temp. (oC)
yield (%)
4a
70
82
90
92
5a
1
—
1-hexene (10)
vinyl acetate (10)
120
120
120
27
9
2
3
10
7
4
sodium acrylate (10) 120
acrylic acid (10) 120
methyl acrylate (10) 120
5
>
>
>
99
<1
<1
<1
8
a
10.0 equiv. of acrylic acid was used. b Neat conditions. c The desilylated phenol
6
99
99
7
acrylic acid (5)
acrylic acid (3)
acrylic acid (5)
acrylic acid (5)
acrylic acid (10)
120
120
80
derivative was also obtained in 27% yield as a by-product.
8
87
Moreover, 3y efficiently underwent dehydrogenation to give
the corresponding phthalic acid derivative (4y) (eq. 1). The
Pd/C-catalyzed dehydrogenative aromatization could also
9
>
99
<1
<1
<1
10
11a
60
80
24
95
smoothly proceed when using various 1,4-cyclohexadienes (3z
-
a 5 mmol of 3a was used.
3ac) prepared from some dienophiles other than dimethyl
acetylenedicarboxylate to give the corresponding arene
The scope of substrates prepared from the corresponding
dienes and dimethyl acetylenedicarboxylate (2a) was next
investigated (Table 2). Various 1-aromatic substituted-2,5-
products (4z-4ac) in excellent yields (eq. 1).
cyclohexadienes
electron-withdrawing groups at the para-position of each
aromatic nucleus ( , R = 1-aromatic ring) efficiently underwent
dehydrogenation to give the corresponding biaryl derivatives
4b 4k
in excellent yields at 80-150 oC. The reducible
functionalities, such as nitro (3f), cyano (3g), aromatic bromide
3h), aromatic chloride (3i), fluoride (3j) and olefin (3k
(
3b-
3k
)
bearing electron-donating or
3
(
- )
(
)
functionalities, never underwent the hydrogenation by in situ-
generated H2. Moreover, 3l or 3m bearing a methoxy group at
the ortho- or meta-position were also transformed into the
desired biaryls (4l and 4m) in excellent yields. Other types of
The Pd/C-catalyzed dehydrogenation of 3a without the H2-
acceptor at 80 oC for 6 h gave 4a in 69% yield accompanied by
the formation of 5a in 30% yield, and the generation of H2 gas
could be detected by gas chromatography thermal
conductivity detector (GC/TCD) (eq. 2). Meanwhile, the
arenes (4n
group or bromo-substituted substrates on the 1,4-
cyclohexadiene ring (3n 3p) could be transformed into the
corresponding arenes 4n 4p). Furthermore, the present
-4p) were also effectively constructed. The siloxy
-
(
-
reaction using 3a (0.1 mmol) and dodecyl acrylate (
mmol) as the H2-acceptor gave 4a in 95%, and 0.077 mmol of
dodecyl propionate ( ) was obtained as the hydrogenated
6) (0.5
dehydrogenation method was applicable for the synthesis of
various heterobiaryls (4q and 4r), terphenyls (4s-4v), and so on
7
(
4w and 4x).
product (eq. 3). These results clearly indicated that the
transformation of cyclohexadienes into arenes proceeded due
to the dehydrogenation process and in situ-generated H2 was
effectively trapped with the acrylic acid derivatives.
Table 2. Scope of substrates for dehydrogenation of 1,4-cyclohexadienes.
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Scheme 2. Proposed reaction mechanisms.
Cyclohexene derivatives (3’a or 3’b), prepared from 2,3-
dimethyl-1,3-butadienes and maleic acid/fumaric acid, were
also efficiently aromatized to the corresponding benzene
derivative (4w) by the Pd/C-catalyzed double dehydrogenation
in excellent yields (eq. 4). It is noteworthy that only the trans-
isomer (3’c-[trans]) was aromatized to 4a, while the cis-isomer
(
3’c-[cis]) remained unchanged by the use of the diastereo The dehydrogenation of further cyclohexene derivatives as
substrates was also investigated (eq.6). The cyclohexene (3’d)
mixture of dimethyl 3-phenylcyclohexene-4,5-dicarboxylate
prepared by Diels-Alder reaction of isoprene and dimethyl
fumalate was efficiently dehydrogenated in excellent yield.
(
3’c) derived from 1-phenyl-1,3-butadiene (1a) and maleic acid
(eq. 5).
Cyclohexene monocarboxylic acid
(
3’e
)
and simple
cyclohexene (3’f) were also efficiently aromatized to the
corresponding products (4ae and 4af; 45% yield of 4af may be
due to the volatile nature). The results of inapplicable
substrates (cyclohexene dicarboxylic acid and cyclohexane
derivatives) are described in the ESI.
The one- pot synthesis of the target molecules is an important
approach to shorten and simplify the synthetic route.9
Although the 1,3-diene derivatives bearing a leaving group
within the molecule, such as methoxy, siloxy or halogen
functionality, could directly transform into the aromatized
benzene derivatives via Diels-Alder reaction with adequate
dienophiles and the following elimination of the leaving
group,10 no dehydrogenated aromatization method has been
reported in the literature.
The present dehydrogenative aromatization of 1,4-
cyclohexadiene derivatives (3) into arenes (4) can proceed via
the oxidative addition of Pd(0) into a comparatively active
C(sp3)-H bond corresponding to the allylic position to form an
intermediate A, which undergoes olefin isomerization to B and
the subsequent β-hydride elimination (Scheme 2, top). The
eliminated H2 is trapped by acrylic acid, and the undesired
Diels-Alder reaction can proceed under solvent-free
Pd/C-catalyzed hydrogenation of
3 is suppressed. The
conditions.11 After Diels-Alder reaction between
1
and
, the subsequent
addition of Pd/C, acrylic acid and H2O and stirring at 120 oC
could directly produce in a one-pot manner (The detailed
optimization process is described in Table S3 in the ESI).
Consequently, various biaryls (4a 4c 4d 4f 4h, and 4j),
2 under
dehydrogenation of the diastereo mixture (3’c) is probably
neat conditions at 50 oC for 12 h to form
3
initiated by the oxidative addition of Pd(0) to the benzylic C-H
bond to form the corresponding intermediates C1 and C3
derived from 3’c-[trans] and 3’c-[cis], respectively (Scheme 2,
bottom). C1 is smoothly converted into another conformer C2
on which the subsequent β-hydride elimination can produce
due to the vicinal positional relationship of the Pd species and
the neighboring hydrogen atom.8 The 1,3-cylohexadiene (
) is
,
4
,
,
,
,
,
D
heterobiaryl (4q), terphenyl (4s), and benzene derivative (4w
)
could be efficiently synthesized.
D
Further chemical transformation of the obtained arene
derivatives ( ) was also investigated (Table 4). Diol derivatives
), resulting from the LiAlH4 reduction of the dicarboxylate
repeatedly dehydrogenated to 4a in a similar manner. On the
other hand, the β-hydride elimination cannot take place on the
intermediates (C3 and C4) based on the spatially distant
positions between the Pd species and the neighboring
hydrogen atom.
4
(
8
methyl esters, were intramolecularly-cyclized by the use of the
PO(OMe)3 and NaH combination12 to give phthalane
derivatives (9)
13 in good yields.
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Table 3. One-pot arene synthesis.a
Conflicts of interest
There are no conflicts to declare.
Notes and references
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under Ar at 50 oC for 12 h, then 10% Pd/C (0.02 mmol, 10 mol%), acrylic acid (1.0
mmol, 5.0 equiv.) and H2O (2 mL) at 120 oC under Ar for 24 h. b 36 h for the 2nd
3
4
c
step. 67% of the cyclohexadiene derivative (3f) was also obtained as an
intermediate.
Table 4. Synthetic application of obtained arene derivatives.a,b
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a
Reaction conditions : step 1; A mixture of 4 (0.2 mmol, 1.0 equiv.) and LiAlH4
(0.8 mmol, 4.0 equiv.) in THF (0.2 mL) was stirred at 0 oC for 10 min under Ar.
Then, the reaction mixture was stirred at room temperature for 24 h. step 2; The
mixture of 8 (0.1 mmol, 1.0 equiv.) and NaH (0.2 mmol, 2.0 equiv.) in cyclopentyl
methyl ether (CPME; 0.5 mL) was stirred at 0 oC for 10 min under Ar. Then,
PO(OMe)3 (0.25 mmol, 2.5 equiv.) was added and stirred at room temperature
for 24 h. b Yields of steps 1 and 2 are described in turn in parentheses.
6
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8
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cyclohexadienes and cyclohexenes in water. Furthermore, the
one-pot arene synthesis could also be accomplished via Diels-
Alder reaction of 1,3-dienes and dienophiles and subsequent
Pd/C-catalyzed dehydrogenation. The results will be practically
applicable as simple, easy and lean synthetic methods for the
materially useful highly-functionalized arenes without any
waste except for H2 gas.
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Acknowledgements
We thank the N. E. Chemcat Corporation for the kind gift of
the various metal on carbon catalysts, and the important
suggestion for the application of this method, the ICP-OES
measurements. This study was supported by Grant-in-Aid for
Scientific Research (C) from the Japan Society for the
Promotion of Science (JSPS: 16K08169 for Y. S.).
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