Palladium(II) Catalyzed cyclization-carbonylation-cyclization coupling reaction of (ortho-Alkynyl Phenyl) (Methoxymethyl) Sulfides using molecular oxygen as the terminal oxidant

Article abstract of DOI:10.3390/molecules21091177

An efficient PdII /Pd0 -p-benzoquinone/hydroquinone-CuCl2 /CuCl catalyst system was developed that uses environmentally friendly molecular oxygen as the terminal oxidant to catalyze the cyclization-carbonylation-cyclization coupling reaction (CCC-coupling

Full text of DOI:10.3390/molecules21091177

molecules
Article
Palladium(II) Catalyzed
Cyclization-Carbonylation-Cyclization Coupling
Reaction of (ortho-Alkynyl Phenyl) (Methoxymethyl)
Sulfides Using Molecular Oxygen as the
Terminal Oxidant
Rong Shen, Taichi Kusakabe, Tomofumi Yatsu, Yuichiro Kanno, Keisuke Takahashi,
Kiyomitsu Nemoto and Keisuke Kato *
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan;
shenrong_927@yahoo.co.jp (R.S.); taichi.kusakabe@phar.toho-u.ac.jp (T.K.); 3014004y@nc.toho-u.ac.jp (T.Y.);
ykanno@phar.toho-u.ac.jp (Y.K.); keisuke.takahashi@phar.toho-u.ac.jp (K.T.);
kiyomitsu.nemoto@phar.toho-u.ac.jp (K.N.)
* Correspondence: kkk@phar.toho-u.ac.jp; Tel.: +81-474-721-805
Academic Editor: Davide Ravelli
Received: 22 July 2016; Accepted: 30 August 2016; Published: 5 September 2016
Abstract: An efficient PdII/Pd0-p-benzoquinone/hydroquinone-CuCl2/CuCl catalyst system was
developed that uses environmentally friendly molecular oxygen as the terminal oxidant to catalyze
the cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of (o-alkynyl
phenyl) (methoxymethyl) sulfides.
Keywords: palladium; carbonylation; molecular oxygen; CCC-coupling reaction; bisoxazoline
1. Introduction
Cascade reactions are important tools for constructing a variety of heterocycles in one step starting
from simple compounds [
coupling reaction (CCC-coupling reaction) of (o-alkynyl phenyl) (methoxymethyl) sulfides
by palladium(II)-bisoxazoline (box) complexes afforded bis(benzothiophen-3-yl) methanones
yield (Scheme 1) [ ]. Nucleophilic attack by the sulfur atom at the electrophilically activated triple
bond is followed by CO insertion to produce the acyl palladium intermediate . The methoxymethyl
group may be removed by acetal exchange (or hydrolysis) during the formation of intermediate
1
–
4
]. Recently, we reported that the cyclization-carbonylation-cyclization
catalyzed
in good
1
2
5
A
A
.
Coordination of the triple bond of a second molecule induces the second cyclization, and reductive
elimination then leads to the formation of a ketone bearing two benzothiophene groups. The efficient
regeneration of the PdII species from Pd0 is the crucial step for obtaining a high yield of the product,
and stoichiometric p-benzoquinone was employed as a re-oxidant in this transformation. However,
there is a disadvantage to using p-benzoquinone: a stoichiometric amount of hydroquinone is
formed as unwanted waste. Molecular oxygen is considered an ideal oxidant because it is naturally
abundant, inexpensive (or free if used as present in the atmosphere), and environmentally friendly,
and does not generate any waste products, thereby fulfilling the requirements of a “green chemistry”
reactant [
6
]. Bäckvall and coworkers have conducted extensive studies of the palladium(II)-mediated
]. p-Benzoquinone is the most
oxidative 1,4-addition of nucleophiles to conjugated dienes [7,8
common stoichiometric oxidant used in these reactions, but Bäckvall and coworkers also developed
a redox-coupled catalytic system to enable the use of molecular oxygen as the terminal oxidant for
aerobic palladium-catalyzed oxidations [9–11].
Molecules 2016, 21, 1177; doi:10.3390/molecules21091177
www.mdpi.com/journal/molecules

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Scheme 1. Our previous work: catalytic cycle of cyclization-carbonylation-cyclization coupling reaction
(CCC-coupling reaction) reaction. Ph, phenyl; MOM, methoxymethyl.
p-Benzoquinone and macrocyclic metal complexes are employed in these oxidations as
electron-transfer mediators (ETMs). ETMs usually facilitate the oxidation reaction by transporting
electrons from the catalyst to the oxidant along a low-energy pathway, thereby increasing
the efficiency of oxidation and thus complementing direct oxidation reactions [12]. Herein, we report
a PdII/Pd0-p-benzoquinone/hydroquinone-CuCl2/CuCl system that uses environmentally friendly
molecular oxygen as the terminal oxidant to catalyze the CCC-coupling reaction of (o-alkynyl phenyl)
(methoxymethyl) sulfides.
2. Results and Discussion
The required starting materials
1 were prepared as described previously [5]. Initially, we selected
1a as a standard substrate to search for potential co-oxidants. The reaction of 1a with [Pd(tfa)2(L2)]
(5 mol %) in methanol under a CO/O2 atmosphere (1:1, balloon) generated the dimeric ketone 2a in
12% yield, along with 2-phenylbenzo[b]thiophene 3a (65% yield) (Table 1, Entry 1). The presence of
reduced metal (Pd0, black) showed that electron transfer between Pd0 and O2 is too slow compared
with decomposition. Next, five co-oxidants (ETMs) were tested in the reaction (p-benzoquinone, CuCl2,
FeCl3 6H2O, and VO(acac)2; acac, acetyl acetonate) (Table 1, Entries 2–5), of which p-benzoquinone
·
and CuCl2 gave encouraging but still unacceptable yields (Table 1, Entries 2 and 3). These results
suggested that one ETM alone has insufficient oxidation potential to oxidize Pd0 by O2 and therefore the
simultaneous use of two co-oxidants was investigated (Table 1, Entries 6–9). Fortunately, the dimeric
ketone 2a was obtained in 87% yield by using p-benzoquinone (10 mol %) and CuCl2 (5 mol %) as
co-oxidants (Table 1, Entry 6). We next attempted to reduce the amount of p-benzoquinone required by
investigating the reaction temperature (Table 1, Entries 7–9). Th◦e best result was obtained by using
p-benzoquinone (5 mol %) and CuCl2 (5 mol %) as co-oxidants at 0 C, affording 2a in 88% yield (Table 1,
Entry 8). Having optimized the reaction conditions, we examined the reaction of various (o-alkynyl
phenyl) (methoxymethyl) sulfide derivatives (Table 2), starting with the reaction of substrates 1b
–h
bearing aryl substituents at the alkyne terminus (Table 2, Entries 1–8). Neither electron-donating nor

Molecules 2016, 21, 1177
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electron-withdrawing groups affected the reaction, and 2b
–d
were obtained in good yield, similar to
that of the parent substrate 1a (Table 2, Entries 2–4). Three different halogen substituents (F, Cl,
and Br) and a thiophene ring were tolerated under the reaction conditions used (Table 2, Entries 5–8).
Substrates 1i
ketones 2j
The scope of the substrate for the CCC-coupling reaction was expanded further by investigating the
reactions of substrates bearing R2 substituents (Table 2, Entries 13–14). The reactions of 1m
bearing
–l
bearing alkyl substituents at the alkyne terminus were transformed to the corresponding
–
l in 71%–92% yield (Table 2, Entries 9–12). Free hydroxyl groups were also tolerated.
–
o
a Cl substituent, methyl group, and methoxy group in an aromatic moiety proceeded well.
Table 1. Optimization of the CCC-coupling reaction of 1a.
Entry
Co-Oxidant
Conditions
Yield of 2 (%) Yield of 3 (%) Recovery (%)
◦
1
2
3
4
5
None
p-BQ (10 mol %)
CuCl2 (5 mol %)
15 C ~rt, 72 h
12
48
46
7
65
19
16
-
trace
-
14
87
32
◦
5
C ~rt, 72 h
5
5
5
◦
◦
◦
C, 24 h
C, 24 h
C, 24 h
FeCl3
·
6H2O (5 mol %)
VO(acac)2 (5 mol %)
p-BQ (10 mol %)
CuCl2 (5 mol %)
p-BQ (5 mol %)
CuCl2 (5 mol %)
p-BQ (5 mol %)
CuCl2 (5 mol %)
p-BQ (5 mol %)
CuCl2 (5 mol %)
31
12
◦
◦
◦
6
7
8
9
5
5
0
C, 24 h
C, 24 h
87
84
88
65
8
7
-
-
C, 48 h
5
-
◦
−5 C, 48 h
trace
20
Table 2. Scope of suitable substrates for the CCC-coupling reaction.
Entry
R1
R2
R3
Substrate Conditions
Yield of 2 (%)
◦
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Ph
4-MePh
4-MeOPh
4-CF3Ph
4-FPh
4-BrPh
4-ClPh
3-Thienyl
Phenethyl
Octyl
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
0
C, 48 h
2a: 88
2b: 84
2c: 93
2d: 83
2e: 80
2f: 82
2g: 82
2h: 80
2i: 92
2j: 71
2k: 90
2l: 84
2m: 80
2n: 96
2o: 82
◦
−10 C, 48 h
◦
−10 C, 48 h
◦
0
C, 48 h
◦
−10 C, 48 h
◦
−10 C, 48 h
◦
−10 C, 48 h
◦
◦
0
0
C, 48 h
C, 48 h
◦
−10 C, 48 h
◦
Cyclopropyl
(CH2)9OH
Ph
−10 C, 48 h
◦
−10 C, 48 h
◦
−10 C, 72 h
◦
Ph
Ph
−10 C, 48 h
◦
−10 C, 48 h

Molecules 2016, 21, 1177
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This redox-coupled PdII/Pd0-p-benzoquinone/hydroquinone-CuCl2/CuCl triple catalytic system
can be described according to Scheme 2. The initial steps of the CCC-coupling reaction are mediated
by PdII [
5] and p-benzoquinone acts as a co-oxidant (ETM) to transfer protons and electrons from
palladium to CuCl2. Finally, CuCl is re-oxidized by molecular oxygen, the terminal oxidant [13,14].
Scheme 2. Proposed redox cycles.
Benzo[b]thiophene skeletons are an important class of S-heterocycles [15–18] and are found in
a variety of drugs, pesticides, and biologically active compounds that exhibit various interesting
biological properties [19
and pharmaceuticals [25
–
24]. Diaryl ketone scaffolds are also important motifs in natural products
–30] (Figure 1). Androgens are known to have beneficial anabolic actions on
various tissues such as bone and muscle. However, the clinical use of androgens has been limited
because of their undesirable sexually actions. Recently, non-steroidal androgens have been investigated
in many laboratories. As a preliminary study, we tested the androgen receptor (AR) agonistic activity
of 2p and 2l. Demethylation of 2o afforded 2p in 63% yield (Scheme 3). We performed androgen
response element (ARE)-driven luciferase reporter assay (ARE-luc.) in human kidney derived HEK293
cells. A portion of 10 µM of 2p and 2l were examined for their ability to activate the transcription of
the ARE-luc. reporter gene (Figure 2). Both 2p and 2l elicited ARE-luciferase reporter activity similarly
to dihydrotestosterone (DHT, 10 nM). This observation suggested that dibenzo[b]thiophenyl ketone
scaffolds (such as 2p and 2l) may expect to be pharmacophores for non-steroidal AR-agonist. We are
currently investigating further biological studies of the synthesized compounds 2.
Figure 1. Some drugs having diarylketone scaffolds.
Scheme 3. Preparation of 2p and the structure of 2l.

Molecules 2016, 21, 1177
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Figure 2. Effect of 2p and 2l on ARE-luciferase reporter activity in HEK293 cells. The results are shown
as the mean ± S.D. (n = 4). ** p < 0.01 compared with the solvent control.
The HEK293 cells were transfected with the ARE-luciferase reporter, AR expression, and pGL4.74
plasmids. The next day, cells were treated with dihydrotestosterone (DHT) (10 nM), 2p (10 M),
or 2l (10 M) for 24 h. Luciferase activity was measured using the Dual-Luciferase Reporter Assay
System. The results are shown as the mean S.D. (n = 4). Statistically significant differences were
µ
µ
±
determined using one-way analysis of variance followed by Dunnett’s multiple comparison test as
the post-hoc test.
3. Experimental
3.1. General Information
1H and 13C-NMR spectra was recorded on JEOL ECS 400 (JEOL, Tokyo, Japan) and JEOL ECA
500 spectrometers (JEOL, Tokyo, Japan) in CDCl3 with Me4Si as an internal reference. When the solvent
was DMSO-d6, solvent peak was used as a reference (2.50 ppm for 1H, and 39.5 ppm for 13C). 13C-NMR
spectra were recorded at 100 MHz. All reagents were purchased from commercial sources and used
without purification. All evaporations were performed under reduced pressure. Silica gel (Kieselgel 60,
Merck, Kenilworth, NJ, USA) was used for column chromatography. CO and O2 were measured and
injected into a balloon using a jumbo syringe (SGE Analytical Science, Milton Keynes, UK).
3.2. Preparation of Substrates
The (o-alkynyl phenyl) (methoxymethyl) sulfides 1a–n were prepared from known o-iodoanilines
using a published procedure, and the spectral data were identical to those described in the literature [5].
3.3. General Procedure for the Reaction of (o-Alkynyl Phenyl) (Methoxymethyl) Sulfides 1
A 30 mL two-necked round-bottom flask containing a magnetic stir bar, (o-alkynyl phenyl)
(methoxymethyl) sulfide (0.4 mmol), p-benzoquinone (2.2 mg, 0.02 mmol), CuCl2 (3.4 mg, 0.02 mmol),
1
and MeOH (3 mL) was fitted with a rubber septum and a three-way stopcock connected to a balloon
filled with CO and O2 (500 mL:500 mL). The apparatus was purged with the gas from the balloon
by pump-filling via the three-way stopcock. A MeOH (1 mL) suspension of [Pd(tfa)2(L2)] (10.3 mg,
0.02 mmol) was added to the stirred solution at an appropriate temperature via a syringe. The residual
catalyst was washed with MeOH (1 mL) twice, and the reaction mixture was stirred for 24–72 h. In most
cases, the dimeric ketones
collected by filtration and washed with cold MeOH (1.5 mL
amount of remaining in the filtrate was recovered by diluting the filtrate with CH2Cl2 (50 mL) and
washing with 5% NaOH (40 mL). The aqueous layer was extracted with CH2Cl2 (25 mL) and the
2
precipitated from the reaction mixture. The resulting precipitate was
×
2) to yield dimeric ketones . The small
2
2

Molecules 2016, 21, 1177
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combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel. The fraction eluted with hexane/EtOAc (100:1)
afforded small amounts of dimeric ketones
those described in the literature [5].
2. The spectral data of products 2a–o were identical to
Preparation of bis(6-hydroxy-2-phenylbenzo[b]thiophen-3-yl)methanone, 2p
To a suspension of sodium hydride (58 mg, 1.2 mmol, 50% in mineral oil) and 1-dodecanethiol
(243 mg, 1.2 mmol) in anhydrous DMF (5 mL) under Ar was added 2o (101.2 mg, 0.2 mmol), and the
mixture was heated at 110 ◦C for 4 h. The mixture was allowed to cool, and was then diluted with
ice-water. The mixture was extracted with CH2Cl2 (30 mL) twice. The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column
chromatography on silica gel. The fraction eluted with EtOAc afforded 2p (60 mg, 63% yield) as
white solid.mp: 259–260 ◦C; 1H-NMR (DMSO-d6):
δ
6.89–6.97 (8H, m), 7.03 (2H, dd, J = 2.4, 8.0 Hz),
106.7 (2C), 115.7 (2C),
7.08–7.14 (4H, m), 7.98 (2H, d, J = 8.8 Hz), 9.79 (2H, s); 13C-NMR (DMSO-d6):
δ
124.3 (2C), 127.6 (4C), 128.4 (2C),128.5 (4C), 132.1 (2C), 132.3 (2C), 132.5 (2C), 139.2 (2C), 146.4 (2C),
155.5 (2C), 188.5; IR (KBr): 3651, 2925, 1734, 1617, 1560, 1541, 1523, 1508 cm−1; HRMS-EI: m/z: [M+]
calcd for C29H18O3S2 478.0697 found 478.0696 (See Supplementary Materials for more details).
3.4. Agonistic Activity of 2p and 2l
The cells were seeded in 48-well plates and transfected with appropriate expression plasmids,
the ARE-luciferase reporter plasmid, AR expression plasmid, and a Renilla pGL4.74 [hRluc/TK]
(Promega, Madison, WI, USA) as an internal standard by the reverse-transfection method using the PEI
Max reagent (Polysciences Inc., Warrington, PA, USA). After overnight incubation in phenol red-free
DMEM containing 5% charcoal-stripped FBS (Promega, Madison, WI, USA), the cells were treated
with various compounds for 24 h before luciferase activity was measured using the Dual-Luciferase
Reporter Assay System (Promega, Madison, WI, USA). Firefly luciferase activities were normalized
against Renilla luciferase activities.
4. Conclusions
In summary, we developed a multistep electron-transfer process involving a “triple-catalysis”
system: a PdII/Pd0-p-benzoquinone/hydroquinone-CuCl2/CuCl catalytic system that uses
environmentally friendly molecular oxygen as the terminal oxidant to effectively catalyze the
CCC-coupling reaction of (o-alkynyl phenyl) (methoxymethyl) sulfides 2. Synthesized compounds 2p
and 2l showed the androgen receptor (AR) agonistic activity. Dibenzo[b]thiophenyl ketone scaffold
may expect to pharmacophore for non-steroidal AR-agonist. We are currently investigating further
biological studies of the synthesized compounds 2.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/21/9/1177/s1.
1H and 13C-NMR spectra of the synthesized compounds.
Acknowledgments: This research was supported by Grant-in-Aid for Scientific Research (C) (15K07871).
Author Contributions: K.K. conceived and designed the experiments; T.Y., Y.K. and K.N. performed the biological
experiments; T.K. analyzed the data; K.T. contributed reagents and materials; R.S. performed the chemical
experiments, and wrote the paper. All authors approved the final manuscript.
Conflicts of Interest: The authors declare no conflict of interest.
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