Catalyzed Cyclization-Carbonylation-Cyclization Coupling Reaction of

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Sep 5, 2016 - Cyclization-Carbonylation-Cyclization Coupling. Reaction of (ortho-Alkynyl Phenyl) (Methoxymethyl). Sulfides Using Molecular Oxygen as the.
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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; [email protected] (R.S.); [email protected] (T.K.); [email protected] (T.Y.); [email protected] (Y.K.); [email protected] (K.T.); [email protected] (K.N.) * Correspondence: [email protected]; 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 [1–4]. Recently, we reported that the cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of (o-alkynyl phenyl) (methoxymethyl) sulfides 1 catalyzed by palladium(II)-bisoxazoline (box) complexes afforded bis(benzothiophen-3-yl) methanones 2 in good yield (Scheme 1) [5]. Nucleophilic attack by the sulfur atom at the electrophilically activated triple bond is followed by CO insertion to produce the acyl palladium intermediate A. The methoxymethyl group may be removed by acetal exchange (or hydrolysis) during the formation of intermediate 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 oxidative 1,4-addition of nucleophiles to conjugated dienes [7,8]. p-Benzoquinone is the most 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

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Scheme1.1.Our Our previous work: catalytic of cyclization-carbonylation-cyclization coupling Scheme previous work: catalytic cycle cycle of cyclization-carbonylation-cyclization coupling reaction reaction (CCC-coupling reaction) reaction. Ph, phenyl; MOM, methoxymethyl. (CCC-coupling reaction) reaction. Ph, phenyl; MOM, methoxymethyl.

p-Benzoquinone and macrocyclic metal complexes are employed in these oxidations as p-Benzoquinone and macrocyclic metal complexes in these electron-transfer mediators (ETMs). ETMs usually facilitateare the employed oxidation reaction byoxidations transportingas electron-transfer mediators ETMs usually the oxidation transporting electrons from the catalyst(ETMs). to the oxidant along afacilitate low-energy pathway, reaction thereby by increasing the electrons from the catalyst to the oxidant along a low-energy pathway, thereby efficiency of oxidation and thus complementing direct oxidation reactions [12]. Herein, weincreasing report a the of oxidation and thus complementing direct oxidation reactions [12]. Herein, we report PdIIefficiency /Pd0-p-benzoquinone/hydroquinone-CuCl 2/CuCl system that uses environmentally friendly amolecular PdII /Pd0 -p-benzoquinone/hydroquinone-CuCl /CuCl system that uses environmentally friendly 2 oxygen as the terminal oxidant to catalyze the CCC-coupling reaction of (o-alkynyl molecular oxygen as the terminal oxidant to catalyze the CCC-coupling reaction of (o-alkynyl phenyl) phenyl) (methoxymethyl) sulfides. (methoxymethyl) sulfides. 2. Results and Discussion 2. Results and Discussion The required starting materials 1 were prepared as described previously [5]. Initially, we The required prepared as described previouslyThe [5].reaction Initially, of we1a selected selected 1a as a starting standardmaterials substrate1 were to search for potential co-oxidants. with 1a as a standard substrate to search for potential co-oxidants. The reaction of 1a with [Pd(tfa) (L2)] 2 [Pd(tfa)2(L2)] (5 mol %) in methanol under a CO/O2 atmosphere (1:1, balloon) generated the dimeric (5ketone mol %) in methanol under a CO/O atmosphere (1:1, balloon) generated the dimeric ketone 2 2a in 12% yield, along with 2-phenylbenzo[b]thiophene 3a (65% yield) (Table 1, Entry 1). 2a Thein 12% yield, along with 2-phenylbenzo[b]thiophene 3a (65% yield) (Table 1, Entry 1). The presence presence of reduced metal (Pd0, black) showed that electron transfer between Pd0 and O2 is too slowof 0 , black) showed that electron transfer between Pd0 and O is too slow compared reduced metal (Pddecomposition. 2 compared with Next, five co-oxidants (ETMs) were tested in the reaction with decomposition. Next, five co-oxidants (ETMs) were tested in the reaction (p-benzoquinone, CuCl (p-benzoquinone, CuCl2, FeCl3·6H2O, and VO(acac)2; acac, acetyl acetonate) (Table 1, Entries 2–5), of2 , FeCl acac,2 acetyl acetonate) (Table 1, Entries 2–5), of which p-benzoquinone 3 ·6H 2 O, and VO(acac) which p-benzoquinone and2 ;CuCl gave encouraging but still unacceptable yields (Table 1, Entries 2 and CuCl gave encouraging but still unacceptable yields (Table 1, Entries 2 and 3). These results 2 and 3). These results suggested that one ETM alone has insufficient oxidation potential to oxidize 0 by O and therefore the 0 suggested that one ETM alone has insufficient oxidation potential to oxidize Pd Pd by O2 and therefore the simultaneous use of two co-oxidants was investigated2(Table 1, Entries simultaneous use ofthe twodimeric co-oxidants was2a investigated (Table Entries 6–9). the dimeric 6–9). Fortunately, ketone was obtained in 1,87% yield by Fortunately, using p-benzoquinone ketone was 87% by using p-benzoquinone (10We mol %)attempted and CuCl2to(5reduce mol %) (10 mol2a%) andobtained CuCl2 (5inmol %)yield as co-oxidants (Table 1, Entry 6). next theas co-oxidants (Table 1, Entry 6). We next attempted to reduce the amount of p-benzoquinone required by amount of p-benzoquinone required by investigating the reaction temperature (Table 1, Entries 7–9). investigating the reaction temperature (Table 1, Entries 7–9).(5The best using The best result was obtained by using p-benzoquinone mol %)result and was CuClobtained 2 (5 molby %) as ◦ C, affording 2a in 88% yield (Table 1, p-benzoquinone molaffording %) and CuCl (5 mol %) as co-oxidants at 0 co-oxidants at 0(5°C, 2a in 88% yield (Table 1, Entry 8). Having optimized the reaction 2 Entry 8). Having optimized the the reaction examinedphenyl) the reaction of various (o-alkynyl conditions, we examined reaction conditions, of various we (o-alkynyl (methoxymethyl) sulfide derivatives (Table 2), starting with the reaction of substrates 1b–h aryl substituents the phenyl) (methoxymethyl) sulfide derivatives (Table 2), starting withbearing the reaction of substratesat1b–h alkyne aryl terminus (Table 2,atEntries 1–8).terminus Neither electron-donating nor electron-withdrawing groups bearing substituents the alkyne (Table 2, Entries 1–8). Neither electron-donating nor affected the reaction, and 2b–d were obtained in good yield, similar to that of the parent substrate

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electron-withdrawing groups affected the reaction, and 2b–d were obtained in good yield, similar to Molecules 2016, 2016, 21, 21, 1177 1177 of 88 33 of that Molecules of the parent substrate 1a (Table 2, Entries 2–4). Three different halogen substituents (F, Cl, and Br) and a 2, thiophene ringThree weredifferent tolerated undersubstituents the reaction(F, 2, Entries 1a (Table (Table 2, Entries 2–4). 2–4). Three different halogen substituents (F,conditions Cl, and and Br) Br)used and (Table thiophene ring 5–8). 1a Entries halogen Cl, and aa thiophene ring were tolerated under the reaction conditions used (Table 2, Entries 5–8). Substrates 1i–l bearing Substrates 1i–l bearing alkyl substituents at the alkyne terminus were transformed to the corresponding were tolerated under the reaction conditions used (Table 2, Entries 5–8). Substrates 1i–l bearing alkyl2j–l substituents at the theyield alkyne terminus were transformed transformed tohydroxyl the corresponding corresponding ketones 2j–l in ketones in 71%–92% (Table 2, Entries 9–12). Freeto groups were also tolerated. alkyl substituents at alkyne terminus were the ketones 2j–l in 71%–92% yield (Table 2, Entries 9–12). Free hydroxyl groups were also tolerated. The scope of the The scope of the substrate the CCC-coupling reaction waswere expanded further The by investigating 71%–92% yield (Table 2,for Entries 9–12). Free hydroxyl groups also tolerated. scope of the the substrate for for the the CCC-coupling CCC-coupling reaction was was expanded expanded further further by by investigating investigating the the reactions reactions of of substrate reaction reactions of substrates bearing R2 substituents (Table 2, Entries 13–14). The reactions of 1m–o bearing 2 substituents (Table 2, Entries 13–14). The reactions of 1m–o bearing a Cl substrates bearing R 2 substrates bearing R group, substituents (Table 2,group Entriesin13–14). The reactions of 1m–o bearing a Cl substituent, methyl and methoxy an aromatic moiety proceeded well. a Cl substituent, methyl methyl group, group, and and methoxy methoxy group group in in an an aromatic aromatic moiety moiety proceeded proceeded well. well. substituent, Table 1. Optimization of of the the CCC-coupling CCC-coupling reaction of 1a. 1a. Table 1. 1. Optimization CCC-couplingreaction reaction of 1a. Table Optimization of of

Entry Entry Entry 11 1 22 2 33 3 44 4 55 5 66 6 7 77 8 88

99

9

Co-Oxidant Co-Oxidant Co-Oxidant None None None p-BQ (10 (10 mol mol %) %) p-BQ p-BQ (10 mol %) 2 (5 mol %) CuCl CuCl22 (5 mol %) CuCl FeCl33··6H ·6H2O (5 mol %) FeCl FeCl 3 6H22O (5 mol %) (5 mol mol %) %) VO(acac)22 (5 VO(acac) VO(acac) 2 p-BQ (10 (10 mol mol %) %) p-BQ CuCl222 (5 CuCl (5 mol mol %) %) CuCl p-BQ (5 mol %) p-BQ (5 mol %) CuCl CuCl222 (5 (5 mol mol %) %) CuCl (5 mol %) p-BQ (5 mol %) p-BQ (5 mol %) p-BQ (5 mol %) CuCl (5 mol mol %) %) CuCl222 (5 (5 mol %) CuCl p-BQ (5 mol %) p-BQ (5 mol %) p-BQ2 (5 CuCl (5 mol mol %) %) (5 mol mol %) %) CuCl22 (5 CuCl

Conditions Yield Yieldofof of2 22(%) (%) Yield Yieldofof of3 33(%) (%) Recovery Recovery(%) (%) Conditions Yield (%) Yield (%) Recovery (%) Conditions 15 °C ~rt, 72 h 12 65 trace 15 °C ~rt, 72 h 12 65 trace 15 ◦ C ~rt, 72 h 12 65 trace 5 °C ~rt, ~rt, 72 h h 48 19 5 ◦5C°C ~rt, 7272 h 4848 1919 -5 °C, 24 h 46 16 14 ◦ 14 5 5C,°C, 2424 hh 4646 1616 14 5C,°C, °C, 24 h 7 87 87 5 ◦5 2424 hh 77 - -87 5C,°C, °C, 24 h 31 12 32 5 ◦5 2424 hh 3131 1212 32 32 5C,°C, °C, 24 h 5 ◦5 2424 hh

87 8787

8 88

- --

5 ◦5C,°C, 2424 hh 5 °C, 24 h

8484 84

77 7

--

0 ◦0C,°C, 4848 hh 0 °C, 48 h

8888 88

55 5

--

−5 ◦ C, 48 h −5 °C, °C, 48 48 h h −5

65 65 65

trace trace trace

20 20 20

Table 2. Scope Scope ofsuitable suitablesubstrates substrates for for the CCC-coupling reaction. Table 2. Scope ofof forthe theCCC-coupling CCC-coupling reaction. Table 2. suitable substrates reaction.

Entry Entry 11 22 33 44 55 66 77 8 8 99 10 10 11 11 12 12 13 13 14 14 15 15

R1 R2 Entry R1 R1 R2 Ph H Ph 14-MePh Ph H H 4-MePh 2 4-MePh H 4-MeOPh H 4-MeOPh H 3 4-MeOPh 4-CF3Ph H 44-CF3Ph 4-CF3 Ph H 4-FPh H 5 4-FPh 4-FPh H 4-BrPh 4-BrPh H H 6 4-BrPh 4-ClPh H 7 4-ClPh 4-ClPh H 3-Thienyl3-ThienylH H 83-Thienyl 9 PhenethylH Phenethyl Phenethyl H 10 Octyl Octyl H Octyl H 11 Cyclopropyl Cyclopropyl H Cyclopropyl H 12 (CH2 )9 OHH (CH 2)9OH (CH2)9OH Ph H 13 Ph Cl 14 Ph Ph Cl Ph Me 15 Ph Ph Me Ph H Ph H

3 R 23 RR H HH H HH H H H H HH H HH H HH H HH H HH HH H HH H HH H HH ClH H H Me H HH OMe OMe

Substrate 3 Substrate Substrate R 1a 1a H 1b 1a H 1b 1b 1c H 1c 1c 1d H 1d 1d 1e 1e H 1e 1f H 1f 1f 1g H 1g 1g 1h 1h H 1h H 1i 1i 1i H 1j 1j 1j H 1k 1k H 1k 1l 1l H 1l 1m 1m H 1m 1n 1n 1o OMe1n 1o 1o

Conditions Conditions Conditions °C, 48 48 h 000°C, ◦ C, 48hh −10 °C, °C, 48 h ◦ −10 −10 C,4848h h −10 °C, °C, 48 h ◦ −10 48 −10 C, 48h h 0 °C, 48 h ◦ 00°C,C,4848h h −10 °C, 48 hh ◦ −10°C,C,4848h −10 ◦ C, −10 °C, 4848h hh −10°C, −10 48 ◦ −10 °C, 48 h −10°C,C,4848h h −10 ◦ C,48 °C, hh 000°C, 4848h ◦ C, 48 h 0 0 °C, 48 h 0 °C,◦ 48 h −10°C, C,4848h h −10 −10 °C, 48 h ◦ C, 48 −10°C, −10 48 h hh −10 °C, 48 ◦ − 10 C, 48 −10 °C, °C, 48 h h −10 −10 ◦ C,4872h h −10 °C, °C, 72 h −10 −10 ◦ C,7248h h −10 °C, 4848h hh ◦ C, −10 48 −10°C, −10 °C, 48 h −10 °C, 48 h

Yield of of 2 (%) Yield Yield of 2 (%) 2 (%) 2a: 88 2a: 88 2a: 88 2b: 84 2b: 84 2b: 84 2c: 93 93 2c: 2c: 93 2d: 83 2d: 83 2d: 83 2e: 80 80 2e: 80 2e: 2f: 82 82 2f: 82 2f: 2g: 82 82 2g: 82 2g: 2h: 80 80 2h: 80 2h: 2i: 92 2i: 92 2i: 92 2j: 71 2j: 71 2j: 71 2k: 90 2k: 90 2k: 90 2l: 84 2l: 84 2m: 80 2l: 84 2m: 80 2n: 962m: 80 2n: 96 96 2o: 82 2n: 2o: 82 2o: 82

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This redox-coupled Pd PdIIII/Pd000-p-benzoquinone/hydroquinone-CuCl -p-benzoquinone/hydroquinone-CuCl2/CuCl triple triple catalytic system system This This redox-coupled redox-coupled PdIIII/Pd /Pd 0-p-benzoquinone/hydroquinone-CuCl22/CuCl /CuCl triple catalytic catalytic system can be be described according to -p-benzoquinone/hydroquinone-CuCl Scheme 2. The The initial steps steps of the the /CuCl CCC-coupling reaction are Thisdescribed redox-coupled Pd /Pd triple catalytic system can according to Scheme can be describedII according to Scheme 2. 2. The initial initial steps of of the 2 CCC-coupling CCC-coupling reaction reaction are are mediated by Pd [5] and p-benzoquinone acts as a co-oxidant (ETM) to transfer protons and can be described according to Scheme 2. The initial steps of the CCC-coupling reaction are mediated II mediated by mediated by Pd PdII [5] [5] and and p-benzoquinone p-benzoquinone acts acts as as aa co-oxidant co-oxidant (ETM) (ETM) to to transfer transfer protons protons and and electrons from palladium to CuCl CuCl 2. Finally, CuCl is is re-oxidized re-oxidized by molecular molecular oxygen, the terminal by PdII [5]from andpalladium p-benzoquinone acts as a co-oxidant (ETM) to transfer protonsoxygen, and electrons from electrons to 2 . Finally, CuCl by electrons from palladium to CuCl2. Finally, CuCl is re-oxidized by molecular oxygen, the the terminal terminal oxidant [13,14]. palladium to CuCl . Finally, CuCl is re-oxidized by molecular oxygen, the terminal oxidant [13,14]. oxidant oxidant [13,14]. [13,14]. 2

Scheme 2. 2. Proposed Proposed redox redox cycles. cycles. Scheme Scheme Scheme 2. 2. Proposed Proposed redox redox cycles. cycles.

Benzo[b]thiophene skeletons are are an important important class of of S-heterocycles [15–18] [15–18] and are are found in in a Benzo[b]thiophene Benzo[b]thiophene skeletons skeletons are an an important class class of S-heterocycles S-heterocycles [15–18] and and are found found in aa Benzo[b]thiophene skeletons are an important class of S-heterocycles [15–18] and are found in variety of drugs, pesticides, and biologically active compounds that exhibit various interesting variety variety of of drugs, drugs, pesticides, pesticides, and and biologically biologically active active compounds compounds that that exhibit exhibit various various interesting interesting a variety of drugs, pesticides, and biologically active compounds that exhibit various interesting biological properties [19–24]. Diaryl ketone scaffolds are also important motifs in natural products biological biological properties properties [19–24]. [19–24]. Diaryl Diaryl ketone ketone scaffolds scaffolds are are also also important important motifs motifs in in natural natural products products biological properties [19–24]. Diaryl ketone scaffolds are also important motifs in natural products and pharmaceuticals [25–30] (Figure 1). Androgens are known to have beneficial anabolic actions and pharmaceuticals pharmaceuticals [25–30] [25–30] (Figure (Figure 1). 1). Androgens Androgens are are known known to to have have beneficial beneficial anabolic anabolic actions and actions and pharmaceuticals [25–30] (Figure 1). Androgens are known to have beneficial anabolic actions on on various tissues such as bone and muscle. However, the clinical use of androgens has been on on various various tissues tissues such such as as bone bone and and muscle. muscle. However, However, the the clinical clinical use use of of androgens androgens has has been been various tissues such as bone and muscle. However, the clinical use of androgens has been limited limited because of of their undesirable undesirable sexually actions. actions. Recently, non-steroidal non-steroidal androgens have have been limited limited because because of their their undesirable sexually sexually actions. Recently, Recently, non-steroidal androgens androgens have been been because of their undesirable sexually actions. Recently, non-steroidal androgens have been investigated investigated in many laboratories. As a preliminary study, we tested the androgen receptor (AR) investigated in many laboratories. As a preliminary study, we tested the androgen receptor (AR) investigated in many laboratories. As a preliminary study, we tested the androgen receptor (AR) in many laboratories. As a preliminary study, we tested the androgen receptor (AR) agonistic activity agonistic activity of 2p and 2l. Demethylation of 2o afforded 2p in 63% yield (Scheme 3). We agonistic agonistic activity activity of of 2p 2p and and 2l. 2l. Demethylation Demethylation of of 2o 2o afforded afforded 2p 2p in in 63% 63% yield yield (Scheme (Scheme 3). 3). We We of 2p and 2l. Demethylation of 2o afforded 2p in 63% yield (Scheme 3). We performed androgen performed androgen androgen response response element element (ARE)-driven (ARE)-driven luciferase luciferase reporter reporter assay assay (ARE-luc.) (ARE-luc.) in in human human performed performed androgen response element (ARE)-driven luciferase reporter assay (ARE-luc.) in human response element (ARE)-driven luciferase reporter assay (ARE-luc.) in human kidney derived HEK293 kidney derived HEK293 cells. A portion of 10 μM of 2p and 2l were examined for their ability to kidney kidney derived derived HEK293 HEK293 cells. cells. A A portion portion of of 10 10 μM μM of of 2p 2p and and 2l 2l were were examined examined for for their their ability ability to to cells. A portion of 10 µM of 2p and 2l were examined for their ability to activate the transcription of activate the transcription of the ARE-luc. reporter gene (Figure 2). Both 2p and 2l elicited activate activate the the transcription transcription of of the the ARE-luc. ARE-luc. reporter reporter gene gene (Figure (Figure 2). 2). Both Both 2p 2p and and 2l 2l elicited elicited the ARE-luc. reporter gene (Figure 2). Both 2p and 2l elicited ARE-luciferase reporter activity similarly ARE-luciferase reporter activity similarly to dihydrotestosterone (DHT, 10 nM). This observation ARE-luciferase reporter reporter activity activity similarly similarly to to dihydrotestosterone dihydrotestosterone (DHT, (DHT, 10 10 nM). nM). This This observation observation ARE-luciferase to dihydrotestosterone (DHT, 10 nM). This observation suggested that dibenzo[b]thiophenyl ketone scaffoldssuggested (such asthat 2p dibenzo[b]thiophenyl and 2l) may may expect ketone to be suggested suggested that that dibenzo[b]thiophenyl dibenzo[b]thiophenyl ketone ketone scaffolds scaffolds (such (such as as 2p 2p and and 2l) 2l) may expect expect to to be be scaffolds (such as 2p and 2l) may expect to be pharmacophores for non-steroidal AR-agonist. We are pharmacophores for non-steroidal non-steroidal AR-agonist. We We are currently currently investigating further further biological pharmacophores pharmacophores for for non-steroidal AR-agonist. AR-agonist. We are are currently investigating investigating further biological biological currently further biological studies ofinvestigating the synthesized compounds 2. studies of the synthesized compounds 2. studies studies of of the the synthesized synthesized compounds compounds 2. 2.

Figure 1. drugs having diarylketone diarylketone scaffolds. 1. Some drugs Figure Figure 1. Some Some drugs having having diarylketone scaffolds. scaffolds.

Scheme 3. Preparation Preparation of 2p 2p and the the structure of of 2l. 2l. Scheme Scheme 3. 3. Preparation of of 2p and and the structure structure of 2l.

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Figure 2. Effect of 2p 2l ARE-luciferase on ARE-luciferase reporter activity in HEK293 results are Figure 2. Effect of 2p andand 2l on reporter activity in HEK293 cells.cells. The The results are shown as the mean (n p= < 4).0.01 ** p compared < 0.01 compared with the solvent control. as shown the mean ± S.D. (n±=S.D. 4). ** with the solvent control.

The HEK293 cells were transfected with the ARE-luciferase reporter, AR expression, and The HEK293 cells were transfected with the ARE-luciferase reporter, AR expression, and pGL4.74 pGL4.74 plasmids. The next day, cells were treated with dihydrotestosterone (DHT) (10 nM), 2p (10 plasmids. The cells were treated withwas dihydrotestosterone (DHT) (10 nM), 2p (10 µM), μM), or 2l (10next μM)day, for 24 h. Luciferase activity measured using the Dual-Luciferase Reporter or Assay 2l (10 System. µM) for The 24 h.results Luciferase activity was measured using the Dual-Luciferase Reporter Assay are shown as the mean ± S.D. (n = 4). Statistically significant differences System. The resultsusing are shown as the meanof±variance S.D. (n =followed 4). Statistically significant differences were were determined one-way analysis by Dunnett’s multiple comparison determined using one-way analysis of variance followed by Dunnett’s multiple comparison test as test as the post-hoc test. the post-hoc test. 3. Experimental 3. Experimental 3.1. General Information 3.1. General Information 1H and 13C-NMR spectra was recorded on JEOL ECS 400 (JEOL, Tokyo, Japan) and JEOL ECA 1 H and 13 C-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 1H, and 39.5 13C). 500solvent spectrometers (JEOL, Tokyo, peak Japan) in CDCl Me4 Si as an ppm internal When was DMSO-d 6, solvent was used as a reference (2.50 for reference. ppmthe for solvent 3 with 1 13 13 13 wasC-NMR DMSO-dspectra peak was used as MHz. a reference (2.50 ppm forpurchased H, and 39.5 ppm for C). sources C-NMR were recorded at 100 All reagents were from commercial 6 , solvent spectra werewithout recorded at 100 MHz. reagents were from commercial sources andgel used and used purification. All All evaporations were purchased performed under reduced pressure. Silica (Kieselgel 60, Merck) used for column chromatography. and Opressure. 2 were measured injected 60, without purification. Allwas evaporations were performed under CO reduced Silica geland (Kieselgel into aKenilworth, balloon using a jumbo syringe (SGE Science, Milton Keynes, Merck, NJ, USA) was used for Analytical column chromatography. CO andUK). O2 were measured and injected into a balloon using a jumbo syringe (SGE Analytical Science, Milton Keynes, UK). 3.2. Preparation of Substrates 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 The (o-alkynyl phenyl) (methoxymethyl) sulfides 1a–n were prepared from known o-iodoanilines in the literature [5]. using a published procedure, and the spectral data were identical to those described in the literature [5]. General Procedurefor forthe theReaction Reactionofof(o-Alkynyl (o-Alkynyl Phenyl) (Methoxymethyl) 3.3.3.3. General Procedure (Methoxymethyl)Sulfides Sulfides1 1 mLtwo-necked two-neckedround-bottom round-bottom flask flask containing phenyl) AA 3030mL containing aamagnetic magneticstir stirbar, bar,(o-alkynyl (o-alkynyl phenyl) (methoxymethyl) sulfide 1 mmol), (0.4 mmol), p-benzoquinone (2.2 mg, 0.02 CuCl mmol),(3.4 CuCl 2 (3.4 mg, (methoxymethyl) sulfide 1 (0.4 p-benzoquinone (2.2 mg, 0.02 mmol), mg, 0.02 mmol), 2 0.02 mmol), and MeOH (3 mL) was fitted with a rubber septum and a three-way stopcock connected and MeOH (3 mL) was fitted with a rubber septum and a three-way stopcock connected to a balloon to awith balloon with CO and O2 (500 mL:500 mL). The apparatus was purged with the gas from filled COfilled and O 2 (500 mL:500 mL). The apparatus was purged with the gas from the balloon the balloon by pump-filling via the three-way stopcock. A MeOH (1 mL) suspension of [Pd(tfa)2(L2)] by pump-filling via the three-way stopcock. A MeOH (1 mL) suspension of [Pd(tfa)2 (L2)] (10.3 mg, (10.3 mg, 0.02 mmol) was added to the stirred solution at an appropriate temperature via a syringe. 0.02 mmol) was added to the stirred solution at an appropriate temperature via a syringe. The residual The residual catalyst was washed with MeOH (1 mL) twice, and the reaction mixture was stirred for catalyst was washed with MeOH (1 mL) twice, and the reaction mixture was stirred for 24–72 h. In most 24–72 h. In most cases, the dimeric ketones 2 precipitated from the reaction mixture. The resulting cases, the dimeric ketones 2 precipitated from the reaction mixture. The resulting precipitate was precipitate was collected by filtration and washed with cold MeOH (1.5 mL × 2) to yield dimeric collected by filtration and washed with cold MeOH (1.5 mL × 2) to yield dimeric ketones 2. The small ketones 2. The small amount of 2 remaining in the filtrate was recovered by diluting the filtrate with amount of 2 remaining in the filtrate was recovered byThe diluting the layer filtrate with CH2 Clwith mL) and 2 (50CH CH2Cl2 (50 mL) and washing with 5% NaOH (40 mL). aqueous was extracted 2Cl2 washing with 5% NaOH (40 mL). The aqueous layer was extracted with CH2 Cl2 (25 mL) and the

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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 2. The spectral data of products 2a–o were identical to those described in the literature [5]. 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 CH2 Cl2 (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; 1 H-NMR (DMSO-d6 ): δ 6.89–6.97 (8H, m), 7.03 (2H, dd, J = 2.4, 8.0 Hz), 7.08–7.14 (4H, m), 7.98 (2H, d, J = 8.8 Hz), 9.79 (2H, s); 13 C-NMR (DMSO-d6 ): δ 106.7 (2C), 115.7 (2C), 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 C29 H18 O3 S2 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. and 13 C-NMR spectra of the synthesized compounds.

1H

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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