Photoinduced generation of acyl radicals from simple aldehydes

Jan 12, 2018 - This valuable radical cyclization reaction gave over 20 coumarin derivatives in moderate to good yields with inexpensive 2-tBu-anthraqu...
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Article Cite This: J. Org. Chem. 2018, 83, 1988−1996

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Photoinduced Generation of Acyl Radicals from Simple Aldehydes, Access to 3‑Acyl-4-arylcoumarin Derivatives, and Evaluation of Their Antiandrogenic Activities Kazuki Kawaai,† Tomoaki Yamaguchi,† Eiji Yamaguchi,*,† Satoshi Endo,‡ Norihiro Tada,† Akira Ikari,‡ and Akichika Itoh*,† †

Laboratory of Pharmaceutical Synthetic Chemistry and ‡Laboratory of Biochemistry, Gifu Pharmaceutical University, 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan S Supporting Information *

ABSTRACT: A novel photocatalysis to construct the 3-acyl4-arylcoumarin framework from simple aldehyde with ynoate is described. The reaction proceeded through an acyl radical intermediate generated by hydrogen atom abstraction from aldehyde, followed by reaction with ynoate and then cyclization to afford coumarins. This valuable radical cyclization reaction gave over 20 coumarin derivatives in moderate to good yields with inexpensive 2-tBu-anthraquinone as a catalyst. In addition, synthetic coumarins were investigated for 5α-dihydrotestosterone (DHT)-induced secretion of prostate-specific antigen (PSA) levels and cell proliferation of androgendependent CWR22Rv1 cells.

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INTRODUCTION

generate an acyl radical from an aldehyde using a combined K2S2O8/TBAB system under thermal reaction conditions. On the other hand, photoinduced reactions with organic photocatalysts have been explored in our laboratory,14 and we have already reported that anthraquinone derivatives (AQNs) are effective in the oxidation of toluenes and benzyl alcohols to benzoates and benzoic acids.15 Plausible mechanisms of these reactions include the generation of benzyl radical species via hydrogen atom abstraction by the excited triplet state of 3 AQN*. Thus, an O-centered radical of 3AQN* can act as a hydrogen atom scavenger. We envisioned that acyl radicals can be generated by applying this catalytic system to benzaldehydes if cleavage of the C−H bond of the aldehyde occurred via 3 AQN*. In addition, 3-acyl-4-arylcoumarins can be synthesized by photocatalytic acyl radical addition to the ynoate in a metalfree fashion. Herein, we describe a metal-free organophotocatalyst-induced oxidative sequential addition/cyclization reaction of alkynoates with aldehyde under mild reaction conditions to furnish biologically active 3-acyl-4-arylcoumarins (Scheme 3). We also investigated the effects of 3-acyl-4arylcoumarins on 5α-dihydrotestosterone (DHT)-induced secretion of prostate-specific antigen (PSA) levels and cell proliferation of androgen-dependent CWR22Rv1 cells.

Coumarin and its derivatives contain a common framework widely found in naturally occurring products and commercially available pharmaceuticals. For instance, 3-acylcoumarins exhibit interesting biological activities as selective and reversible MAOB (monoamine oxidase-B) inhibitors,1 and 3-acyl-4-arylcoumarins exhibit anticancer activity through caspase-independent apoptosis.2 They are potential drug candidates for Parkinson’s disease3 and anticancer agents.4 In addition to medicinal applications, functionalized molecules bearing coumarin moieties have been used as fluorescent probes for biothiols.5 Besides traditional methods such as the Perkin/Knoevenagel condensation,6 Pechmann reaction,7 Mizorogi-Heck/lactonization,8 Kostanecki reaction,9 and Wittig reaction,10 several efficient synthetic methods have been documented under the promotion of transition or heavy metal reagents (Scheme 1).11 The controlled generation of highly reactive chemical species is a fundamental strategy for constructing molecules in a straightforward fashion. The addition of in situ generated radicals to a C−C triple bond affords highly reactive vinyl radicals, and subsequent addition of these to other C−C unsaturated bonds affords cyclic compounds. On the basis of this strategy, various methods leading to coumarins, using aryl alkynoates with a radical precursor, were developed (Scheme 2).12 Especially, employing acyl radicals in coumarin synthesis under this strategy is a fundamental way to produce biologically attractive 3-acylcoumarins.13 According to this scenario, Wu and co-workers reported metal-free tandem oxidative acylation/ cyclization between alkynoates and aldehydes, leading to 3-acyl4-arylcoumarins.12g The method involves C−H abstraction to © 2018 American Chemical Society

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RESULT AND DISCUSSION We examined the radical addition/cyclization of phenyl 3phenyl-2-propynate (1a) with p-tolualdehyde (2a) as model substrate, using photocatalyst to optimize the reaction Received: November 19, 2017 Published: January 12, 2018 1988

DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996

Article

The Journal of Organic Chemistry Scheme 1. Synthesis of Coumarin through Classical Transformation

Scheme 2. Synthesis of Coumarin through in Situ Generated C-Centered Radical Addition/Cyclization of Ynoate

Table 1. Optimization of the Reaction Conditions

Scheme 3. Working Hypothesis and This Work

catalyst

oxidant

additive

3aa (%)a

2- Bu-AQN Eosin Y Ru(bpy)3Cl2 2-tBu-AQN 2-tBu-AQN 2-tBu-AQN 2-tBu-AQN 2-tBu-AQN 2-tBu-AQN 2-tBu-AQN 2-tBu-AQN

BPO BPO BPO K2S2O8 H2O2 DTBP BPO BPO BPO

K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 Na2CO3 KOH Et3N K2CO3 K2CO3

(74) 68 38 15 24 30 43 35 43 16 0b

entry 1 2 3 4 5 6 7 8 9 10 11

conditions. Key results are summarized in Table 1 (see the Supporting Information for more details). Fortunately, when we carried out the reaction using 10 mol % 2-tertbutylanthraquinone (2-tBu-AQN) as the catalyst, benzoyl peroxide (BPO) as an oxidant, and potassium carbonate with visible light irradiation, the desired product 3aa was obtained in 76% isolated yield, along with complete regioselectivity (Table

t

BPO

a

Yields were determined by 1H NMR analysis of crude reaction mixture using 1,1,2,2-tetrachloroethane as an internal standard. Number in parentheses refers to isolated yield. bReaction performed in the dark.

1989

DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996

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The Journal of Organic Chemistry 1, entry 1). As regards the photocatalysts, Eosin Y was found to give the product in moderate yield, but a commonly used photocatalyst, tris(bipyridine)ruthenium(II) chloride, was found to be ineffective (entries 2 and 3). Other oxidants, such as K2S2O8, hydrogen peroxide, and di-tert-butyl peroxide (DTBP), led to a decrease in the product yield (entries 4−6). Various bases were also investigated, revealing that K2CO3 is the most efficient base compared to other bases (entries 7−9). On the other hand, the desired product was observed in low yield without an oxidant (entry 10). These results suggest that the combination of a photocatalyst with an oxidant is crucial for the reaction. Control experiments revealed that visible light irradiation is necessary for the reaction to progress (entry 11). With the optimal reaction conditions in hand (Table 1, entry 1), we investigated the generality of the photocatalytic reaction. Initially, the scope of aldehydes bearing various substituents (2) was demonstrated using ynoate 1a as the model substrate (Table 2). The desired coumarins were obtained in good yield

Scheme 4. Acylation/Cyclization/Migration of 2d with pMethyl Alkynoate 1c

On the basis of the result, p-substituted ynoate 1b−g was employed as substrates for the acylation/cyclization/migration reaction (Table 3). A para-substituted phenoxy ring with either Table 3. Acylation/Cyclization/Migration of 2a with Various Alkynoates 1

Table 2. Acylation/Cyclization of 1a with Various Aldehydesa

entry

2

Ar

3

yield (%)b

1 2 3 4 5 6 7c 8 9c 10c 11c

2a 2b 2c 2d 2e 2f 2g 2h 2i 2j 2k

4-Me-C6H4 4-tBu-C6H4 4-MeO-C6H4 C6H5 4-F-C6H4 4-Cl-C6H4 4-CF3-C6H4 3-Me-C6H4 3-MeO-C6H4 3-Cl-C6H4 2-Me-C6H4

3aa 3ab 3ac 3ad 3ae 3af 3ag 3ah 3ai 3aj 3ak

74 74 67 71 66 58 58 77 47 52 70

a

Reaction conditions: mixture of 1a (0.10 mmol), 2 (1.0 mmol), 2-tBu-AQN (10 mol %), benzoyl peroxide (200 mol %), and K2CO3 (50 mol %) in tamyl alcohol (1 mL) was stirred for 20 h under an argon atmosphere irradiated with four 23 W fluorescent lamps. b Isolated yields. cEtOAc was used as solvent instead of tamyl alcohol.

when electron-rich benzaldehydes were employed as acyl radical precursors (entries 2 and 3). Unsubstituted benzaldehyde was also suitable for the reaction (entry 4). A radical precursor such as benzaldehyde bearing an electron-withdrawing group at the para position also worked well, albeit with moderate yield (entries 5−7). Functional groups substituted at the meta and ortho positions of the benzene ring were also tolerated, with the annulation products furnished in 47−77% isolated yield (entries 8−11). We then proceeded to examine the scope and generality of the reaction of substituted ynoate 1 with aldehyde 2d. To our surprise, when p-substituted alkynoate 1c was employed as the substrate, the reaction gave the unexpected product 3cd, but an anticipated one 3cd′ (Scheme 4). The result indicated that the radical acylation, 5-exo-trig cyclization, and 1,2-ester migration, which was consistent with a previous related report, should take place in the reaction to furnish the product.12

a c

Isolated yields. bEtOAc was used as solvent instead of tamyl alcohol. The reaction was performed for 40 h.

electron-donating groups (methyl-, methoxy) or electronwithdrawing groups (iodo, ester, acetyl, and acetoxy) attached to the benzene ring gave the corresponding 1,2-ester migration products (3ba−3ga) in moderate to good yields specifically (entries 1−6). We further explored the scope of the reaction by using msubstituted ynoate 1 as a substrate (Table 4). The desired coumarin (3ha) was obtained as the sole product when the alkynoate with methoxy at the meta position of the phenoxy ring was employed (entry 1). By contrast, with other substituents, such as Br or Me, on the phenoxy ring, two regioisomers were furnished and the major compounds were 1990

DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996

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The Journal of Organic Chemistry Table 4. Acylation/Cyclization/Migration of 2a with Various m-Substituted Alkynoates 1

a

Scheme 6. Control Experiments

isotope effect (eqs 2 and 3). The parallel kinetic isotope effect (KIE) (kH/kD = 1.84) was measured by using 2c and 2c-d1, and this value implies that cleavage of the C−H bond is not the rate-determining step in the reaction mechanism. Moreover, the KIE rate observed is similar to two previously reported parallel KIE rates (kH/kD = 1.84), which were measured for the reaction of an O-centered radical such as tbutoxyl with benzaldehyde/d6-benzaldehyde.16 Competing experiments with p-anisaldehyde 2c and 4-fluorobenzaldehyde 2e were performed to reveal the electronic effect of the aldehyde. As a result, coumarin 3ac, which was generated by reaction with 2c, was observed as a major product, and the electron-rich aldehyde was superior to the electron-poor aldehyde, as reported previously.17 To evaluate the role of BPO, the reaction was performed without catalyst (eq 5). Although the yield of 3aa was significantly decreased to 0% at room temperature, the corresponding product was obtained in 54% yield under thermal conditions. This result indicated that BPO was decomposed under thermal conditions and that the benzoyloxy radical generated acted as a hydrogen atom abstraction agent. From both the overall results above and previously published literature, two plausible mechanisms are depicted in Scheme 7.12 Initially, acyl radical I was generated through hydrogen atom abstraction from the parent aldehyde by photogenerated 3 AQN*. The resultant AQH· was reoxidized with BPO to regenerate AQN and form a benzoyloxy radical. Then, reaction of I with ynoate 1 leads to vinyl radical intermediate II, which undergoes 5-exo-trig cyclization to afford spirocyclic intermediate III. The generated III was readily oxidized to form

Isolated yields.

reacted at less sterically hindered positions compared to the minor products (3ia, 3ia′, 3ja, and 3ja′). Although the desired coumarin was not confirmed when employing an ortho-substituted alkynoate with methoxy on the phenoxy moiety 1k, reaction at the ipso position of the methoxy group proceeded to afford 3aa in 70% yield (Scheme 5). Scheme 5. Acylation/Cyclization/Migration of 2a with oMeO Alkynoate 1k

To gain insight into the reaction mechanism, several control experiments were conducted, as shown in Scheme 6. For the first control experiment, we added radical-trapping reagents, TEMPO and BHT, into the reaction mixture. The reaction was found to be completely suppressed with no desired product being obtained, and a radical-trapping product 2a-TEMPO was detected by GC−MS (eq 1). This result suggested that our strategy involved acyl radical generation. We assumed that AQN was initially affected by benzaldehydes due to alkynoates 2a but was completely recovered when the reaction was conducted without aldehydes. We then investigated the kinetic 1991

DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996

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The Journal of Organic Chemistry Scheme 7. Plausible Reaction Mechanisms

Figure 1. Inhibitory effects of the compounds on proliferation of androgen-dependent prostate cancer CWR22Rv1 cells. (A) PSA mRNA level. The cells were pretreated for 2 h with the indicated 50 μM of 3 or the vehicle, DMSO, and then treated with 1 nM 5α-DHT for 24 h. The expression level of PSA in the cells was analyzed by quantitative RT-PCR analysis. (B) Cell proliferation. The cells were pretreated for 2 h with the indicated 50 μM of 3 or the vehicle, DMSO, and then treated with 1 nM 5α-DHT for 72 h. The viability is expressed as a percentage of the value in the control cells. ##p < 0.01, significantly different from the control cells that were treated with vehicle alone. **p < 0.01, *p < 0.05, significantly different from the cells that were treated with 5α-DHT alone.

carbocation intermediate III′ under the reaction condition. 1,2Ester migration of III′ could proceed to form IV, and the process is able to explain the formation of unexpected cyclization products 3ba−3ja′ (Tables 3 and 4). Finally, aromatization of IV furnishes the corresponding 3-acyl-4arylcoumarin 3 (route 1). The other possible mechanism is acyl radical generation mediated by a benzoyloxy radical, which is generated by photo or thermal decomposition of BPO (route 2). The biological efficacies of synthetic 3-acyl-4-arylcoumarins 3 were investigated by analyzing their effects on cellular PSA levels and the proliferation of androgen-dependent prostate cancer CWR22Rv1 cells. Among the 11 compounds, all except for 3fa and 3ga significantly inhibited PSA secretion and cell growth induced by 1 nM 5α-DHT, and 3ja produced the largest decrease in PSA levels (Figure 1). As 3fa and 3ga, with a bulky substituent on the 4-phenylcoumarine moiety at the 7position, showed significantly less inhibitory potency in androgen-dependent PSA secretion and proliferation than compounds with less bulky 3ba or without substituent 3aa, the bulky substituents of 3fa and 3ga might diminish the antiproliferative potency of the compounds against CWR22Rv1 cells. The results imply that all the compounds except for 3fa and 3ga inhibited androgen-induced prostate cancer cell proliferation through antagonistic activity against androgen receptors.

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CONCLUSION In conclusion, we have achieved the novel formation of acyl radicals and access to coumarin derivatives under visible light irradiation. Our methodology uses harmless visible light, a cheap and commercially available photocatalyst, and simple aldehydes as radical sources. Further applications of the radicals for other substrates is being studied at our laboratory. In future work, we will aim to further understand the mechanisms involved in the antiproliferative activity against androgen-dependent prostate cancer cells; our synthesis and evaluation results for the coumarins studied indicate their efficacy as potential candidates for new therapeutics.

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EXPERIMENTAL SECTION

General Methods. Unless otherwise noted, all reactants or reagents including dry solvents were obtained from commercial suppliers and used as received. Flash column chromatography was performed with a YMC-GEL SIL 8 nm S-25 um (SLF 08S25). Analytical thin-layer chromatography (TLC) was carried out using 0.25 mm commercial silica gel plates (Merck silica gel 60 F254). The developed chromatogram was analyzed by a UV lamp (254 nm). 1H 1992

DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996

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The Journal of Organic Chemistry

3-(4-Fluorobenzoyl)-4-phenyl-2H-chromen-2-one (3ae).20 Purification by flash chromatography on silica gel (Rf = 0.16 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.31). 3ae was obtained as a yellow solid (22.7 mg, 66% yield, 6.6 × 10−2 mmol). 1H NMR (400 MHz, CDCl3) δ 7.84−7.81 (m, 2H), 7.63 (ddd, J = 8.2, 6.8, 1.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.37−7.24 (m, 7H), 7.03 (t, J = 8.7 Hz, 2H). 13C NMR (125 MHz, CDCl3) δ 190.5, 166.1 (d, J = 255.5 Hz), 158.7, 153.7, 153.1, 132.8, 132.7 (d, J = 2.4 Hz), 132.2, 132.0 (d, J = 9.6 Hz), 129.6, 128.6, 128.0, 125.6, 124.7, 119.3, 117.2, 115.9 (d, J = 21.6 Hz). (one carbon merged to others) 19F NMR (470 MHz, CDCl3) δ −103.2. HRMS: m/z (DART) calcd for C22H14O3F (M + H)+ 345.0921, found 345.0909. 3-(4-Chlorobenzoyl)-4-phenyl-2H-chromen-2-one (3af).20 Purification by flash chromatography on silica gel (Rf = 0.23 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3af was obtained as a yellow solid (20.8 mg, 58% yield, 5.8 × 10−2 mmol). 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.7 Hz, 2H), 7.63 (ddd, J = 8.2, 6.8, 1.9 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.37−7.24 (m, 9H). 13 C NMR (100 MHz, CDCl3) δ 191.0, 158.8, 153.8, 153.4, 140.4, 134.6, 132.9, 132.2, 130.6, 129.7, 129.0, 128.7, 128.7, 128.1, 125.5, 124.8, 119.3, 117.3. HRMS: m/z (DART) calcd for C22H14O3Cl (M + H)+ 361.0626, found 361.0633. 4-Phenyl-3-(4-trifluoromethylbenzoyl)-2H-chromen-2-one (3ag).20 Purification by flash chromatography on silica gel (Rf = 0.19 in n-hexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.31). 3ag was obtained as a yellow solid (22.8 mg, 58% yield, 5.8 × 10−2 mmol). 1H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.2 Hz, 2H), 7.68−7.63 (m, 3H), 7.50 (d, J = 8.2 Hz, 1H), 7.38−7.25 (m, 7H). 13C NMR (125 MHz, CDCl3) δ 191.2, 158.6, 153.9, 153.7, 138.8, 134.7 (q, J = 32.4 Hz), 133.1, 132.0, 129.7, 129.4, 128.7, 128.6, 128.1, 125.6, 125.1, 124.8, 123.4 (q, J = 272.3 Hz), 119.2, 117.2. 19F NMR (470 MHz, CDCl3) δ −63.1. HRMS: m/z (DART) calcd for C23H14O3F3 (M + H)+ 395.0890, found 395.0901. 3-(3-Methylbenzoyl)-4-phenyl-2H-chromen-2-one (3ah).21 Purification by flash chromatography on silica gel (Rf = 0.14 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ah was obtained as a yellow solid (26.3 mg, 77% yield, 7.7 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.62−7.56 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H), 7.34−7.28 (m, 4H), 7.25−7.20 (m, 4H), 7.15−7.10 (m, 2H), 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 193.7, 158.8, 153.6, 152.3, 140.1, 135.8, 132.6, 132.4, 132.4, 131.9, 131.1, 129.3, 128.5, 128.4, 127.9, 127.4, 125.5, 124.6, 119.5, 117.1, 21.3. HRMS: m/z (DART) calcd for C23H17O3 (M + H)+ 341.1172, found 341.1181. 3-(3-Methoxybenzoyl)-4-phenyl-2H-chromen-2-one (3ai).20 Purification by flash chromatography on silica gel (Rf = 0.18 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ai was obtained as a yellow solid (16.7 mg, 47% yield, 4.7 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.62 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.47 (dd, J = 8.0, 1.2 Hz, 1H), 7.38−7.34 (m, 5H), 7.30−7.24 (m, 5H), 7.06 (ddd, J = 8.0, 2.3, 1.2 Hz, 1H), 3.78 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.0, 159.7, 158.8, 153.7, 152.9, 137.4, 132.7, 132.3, 129.6, 129.5, 128.7, 128.6, 128.0, 126.0, 124.6, 122.5, 120.7, 119.4, 117.2, 112.6, 55.4. HRMS: m/z (DART) calcd for C23H17O4 (M + H)+ 357.1172, found 357.1167. 3-(3-Chlorobenzoyl)-4-phenyl-2H-chromen-2-one (3aj).20 Purification by flash chromatography on silica gel (Rf = 0.20 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3aj was obtained as a yellow solid (18.7 mg, 52% yield, 5.2 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.74 (t, J = 1.7 Hz, 1H), 7.68−7.62 (m, 2H), 7.49−7.46 (m, 2H), 7.38−7.35 (m, 3H), 7.33−7.25 (m, 5H). 13 C NMR (125 MHz, CDCl3) δ 190.9, 158.6, 153.7, 153.6, 137.6, 134.9, 133.7, 133.0, 132.1, 129.9, 129.7, 129.0, 128.7, 128.6, 128.1, 127.3, 125.2, 124.8, 119.2, 117.3. HRMS: m/z (DART) calcd for C22H14O3Cl (M + H)+ 361.0626, found 361.0639. 3-(2-Methylbenzoyl)-4-phenyl-2H-chromen-2-one (3ak).20 Purification by flash chromatography on silica gel (Rf = 0.23 in nhexane:toluene:ethyl acetate:acetic acid = 7:7:1:0.15). 3ak was obtained as a yellow solid (24.0 mg, 70% yield, 7.0 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.64−7.59 (m, 3H), 7.47 (dd, J = 8.6,

NMR, 13C NMR, and 19F NMR spectra were obtained on a JEOL ECA 500 spectrometer (500 MHz for 1H NMR, 125 MHz for 13C NMR, and 470 MHz for 19F NMR) and a JEOL AL 400 spectrometer (400 MHz for 1H NMR, 100 MHz for 13C NMR). Chemical shifts (δ) are expressed in parts per million and are internally referenced [0.00 ppm (tetramethylsilane) for 1H NMR and 77.0 ppm (CDCl3) for 13C NMR]. High-resolution mass spectra (HRMS) were obtained on a JEOL JMS-T100TD and are reported as m/z (relative intensity). Melting points were measured on a Yanaco micro melting point apparatus and are uncorrected. IR spectra were recorded on a PerkinElmer Spectrum 100 FTIR spectrometer and are reported in terms of frequency of absorption (cm−1). Preparation of Substrates. Alkynoates (1a, 1b, 1c, 1d, 1e, 1f, 1g) were prepared using modified literature procedures.18 General Procedure for Synthesis of 3. To a Pyrex test tube (1.5 cm × 14.5 cm) were added ynoate (1) (0.10 mmol), aldehyde (2) (1.0 mmol, 10 equiv), 2-tert-butyl-anthraquinone (1.0 × 10−2 mmol, 10 mol %), benzoyl peroxide (0.2 mmol), potassium carbonate (5.0 × 10−2 mmol, 50 mol %), and tert-amyl alcohol (1.0 mL). The reaction tube was degassed through the freeze−pump−thaw cycles for three times; then it was backfilled with argon. The mixture was stirred at ambient temperature for 20 h irradiated with four 23 W fluorescent lamps placed at ca. 7.0 cm from the test tube. The reaction was quenched with saturated aqueous NaHCO3 and extracted with Et2O (20 mL × 3). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to furnish the desired product. 3-(4-Methylbenzoyl)-4-phenyl-2H-chromen-2-one (3aa).19 Purification by flash chromatography on silica gel (Rf = 0.21 in nhexane:toluene:ethyl acetate:acetic acid = 7:7:1:0.15). 3aa was obtained as a yellow solid (25.0 mg, 74% yield, 7.4 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.61 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.47 (dd, J = 8.6, 1.2 Hz, 1H), 7.35−7.23 (m, 7H), 7.16 (d, J = 8.0 Hz, 2H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.6, 158.8, 153.7, 152.7, 144.9, 133.7, 132.6, 132.3, 129.4, 129.3, 128.7, 128.5, 127.9, 126.1, 124.6, 119.5, 117.1, 21.8. (one carbon merged to others) HRMS: m/z (DART) calcd for C23H17O3 (M + H)+ 341.1172, found 341.1173. 3-[4-(1,1-Dimethylethyl)benzoyl]-4-phenyl-2H-chromen-2-one (3ab). Purification by flash chromatography on silica gel (Rf = 0.17 in n-hexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ab was obtained as a yellow solid (28.4 mg, 74% yield, 7.4 × 10−2 mmol). 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 8.6 Hz, 2H), 7.61 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.47 (dd, J = 8.6, 1.2 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.35−7.34 (m, 3H), 7.30−7.23 (m, 4H), 1.29 (s, 9H). 13C NMR (125 MHz, CDCl3) δ 191.7, 158.9, 157.6, 153.6, 152.8, 133.6, 132.6, 132.3, 129.4, 129.2, 128.7, 128.5, 127.9, 126.2, 125.6, 124.6, 119.5, 117.1, 35.2, 30.9. m.p.: 178.0−178.6 °C. HRMS: m/z (DART) calcd for C26H23O3 (M + H)+ 383.1642, found 383.1644. FTIR: (ATR) 3062, 2964, 2869, 1713, 1668, 1604, 1564, 1356, 1266 cm−1. 3-(4-Methoxybenzoyl)-4-phenyl-2H-chromen-2-one (3ac).20 Purification by flash chromatography on silica gel (Rf = 0.23 in nhexane:toluene:ethyl acetate:acetic acid = 7:7:1:0.15). 3ac was obtained as a yellow solid (23.7 mg, 67% yield, 6.7 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.6 Hz, 2H), 7.61 (ddd, J = 8.6, 6.9, 1.7 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.35−7.23 (m, 7H), 6.83 (d, J = 8.6 Hz, 2H), 3.82 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 190.6, 164.2, 159.0, 153.7, 152.5, 132.6, 132.5, 131.8, 129.5, 129.4, 128.7, 128.6, 127.9, 126.2, 124.6, 119.5, 117.2, 113.9, 55.5. HRMS: m/ z (DART) calcd for C23H17O4 (M + H)+ 357.1121, found 357.1108. 3-Benzoyl-4-phenyl-2H-chromen-2-one (3ad).20 Purification by flash chromatography on silica gel (Rf = 0.16 in n-hexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ad was obtained as a yellow solid (23.0 mg, 71% yield, 7.1 × 10−2 mmol). 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.62 (ddd, J = 8.0, 7.5, 1.7 Hz, 1H), 7.52− 7.46 (m, 2H), 7.38−7.24 (m, 9H). 13C NMR (125 MHz, CDCl3) δ 192.1, 158.8, 153.7, 152.9, 136.1, 133.8, 132.7, 132.3, 129.5, 129.2, 128.7, 128.6, 128.6, 127.9, 125.9, 124.6, 119.4, 117.2. HRMS: m/z (DART) calcd for C22H15O3 (M + H)+ 327.1016, found 327.1008. 1993

DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996

Article

The Journal of Organic Chemistry

as a white solid (23.7 mg, 62% yield, 6.2 × 10−2 mmol). 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 1.7 Hz, 1H), 7.80 (dd, J1 = 8.0 Hz, J2 = 1.7 Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.40−7.36 (m, 4H), 7.27−7.26 (m, 2H), 7.18 (d, J = 8.0 Hz, 2H), 2.68 (s, 3H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 196.4, 191.1, 158.4, 153.5, 151.6, 145.2, 139.7, 133.4, 131.8, 129.7, 129.4, 129.4, 128.7, 128.6, 128.3, 128.0, 123.7, 122.9, 117.0, 26.9, 21.8. m.p.: 213.5−214.1 °C. HRMS: m/z (DART) calcd for C25H18O4 (M + H)+ 383.1205, found 383.1205. FTIR: (ATR) 2928, 1721, 1670, 1605, 1355, 1267 cm−1. 3-(4-Methylbenzoyl)-6-methylester-4-phenyl-2H-chromen-2-one (3ga). Purification by flash chromatography on silica gel (Rf = 0.35 in n-hexane:toluene:ethyl acetate:acetic acid = 5:5:1:0.1). 3ga was obtained as a white solid (30.2 mg, 76% yield, 7.6 × 10−2 mmol). 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 8.2 Hz, 2H), 7.37−7.35 (m, 4H), 7.28−7.27 (m, 2H), 7.17 (d, J = 7.7 Hz, 2H), 3.99 (s, 3H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.2, 165.5, 158.3, 153.2, 151.6, 145.2, 133.6, 133.4, 131.8, 129.7, 129.4, 128.7, 128.6, 128.0, 127.9, 125.1, 122.9, 118.2, 52.8, 21.8. (one carbon merged to others) m.p.: 169.0−170.8 °C. HRMS: m/z (DART) calcd for C25H18O5 (M + H)+ 399.1154, found 399.1156. FTIR: (ATR) 3390, 2953, 1717, 1671, 1606, 1557, 1435, 1420, 1359, 1277, 1230, 1095 cm−1. 3-(4-Methylbenzoyl)-7-methoxyl-4-phenyl-2H-chromen-2-one (3ha). Purification by flash chromatography on silica gel (Rf = 0.15 in n-hexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ha was obtained as a yellow solid (18.5 mg, 50% yield, 5.0 × 10−2 mmol). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 9.2 Hz, 1H), 7.35−7.33 (m, 3H), 7.28−7.27 (m, 2H), 7.20−7.15 (m, 3H), 6.71 (d, J = 2.9 Hz, 1H), 3.71 (s, 3H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.8, 159.0, 156.1, 152.4, 148.1, 144.9, 133.7, 132.4, 129.5, 129.4, 129.3, 128.6, 126.5, 120.0, 119.7, 118.1, 110.7, 55.8, 21.8. (one carbon merged to others) m.p.: 154.7−155.4 °C. HRMS: m/z (DART) calcd for C24H19O4 (M + H)+ 371.1278, found 371.1268. FTIR: (ATR) 3060, 2924, 2853, 1711, 1670, 1604, 1566, 1359, 1267, 1235, 1037 cm−1. 5-Bromo-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one (3ia). Purification by flash chromatography on silica gel (Rf = 0.17 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ia was obtained as a yellow solid (7.4 mg, 18% yield, 1.8 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.84 (dd, J = 8.0, 1.7 Hz, 1H), 7.69 (d, J = 8.0 Hz, 2H), 7.35−7.32 (m, 3H), 7.25−7.21 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 8.0 Hz, 1H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.1, 157.7, 152.3, 150.4, 145.1, 136.0, 133.5, 132.1, 129.6, 129.5, 129.4, 128.6, 127.2, 126.9, 125.1, 121.0, 110.9, 21.8. (one carbon merged to others) m.p.: 201.6−202.2 °C. HRMS: m/z (DART) calcd for C23H16O3Br (M + H)+ 419.0277, found 419.0925. FTIR: (ATR) 3062, 2923, 2854, 1725, 1669, 1605, 1555, 1442, 1348, 1056, 975 cm−1. 7-Bromo-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one (3ia′). Purification by flash chromatography on silica gel (Rf = 0.27 in n-hexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ia′ was obtained as a white solid (12.3 mg, 29% yield, 2.9 × 10−2 mmol). 1H NMR (400 MHz, CDCl3) δ 7.71−7.67 (m, 3H), 7.39−7.34 (m, 5H), 7.26−7.24 (m, 2H), 7.17 (d, J = 8.7 Hz, 2H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.2, 158.3, 152.6, 151.6, 145.3, 135.5, 133.6, 131.7, 130.2, 129.9, 129.5, 128.9, 128.7, 127.2, 121.3, 119.0, 117.6, 21.9. (one carbon merged to others) m.p.: 219.8−220.1 °C. HRMS: m/z (DART) calcd for C23H16O3Br (M + H)+ 419.0277, found 419.0282. FTIR: (ATR) 3425, 3062, 2919, 2850, 2121, 1898, 1713, 1667, 1603, 1557, 1352, 1259, 1060, 968 cm−1. 3-(4-Methylbenzoyl)-5-methyl-4-phenyl-2H-chromen-2-one (3ja). Purification by flash chromatography on silica gel (Rf = 0.16 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ja was obtained as a yellow solid (8.3 mg, 23% yield, 2.3 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.71 (d, J = 8.6 Hz, 2H), 7.46 (dd, J = 7.5, 1.2 Hz, 1H), 7.33−7.31 (m, 3H), 7.26−7.24 (m, 2H), 7.17−7.09 (m, 4H), 2.55 (s, 3H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.8, 158.9, 153.0, 152.0, 144.8, 133.9, 133.8, 132.7, 129.4, 129.3, 128.7, 128.4, 126.6, 125.9, 125.7, 124.0, 119.2, 21.8, 15.7. (one carbon merged to others) m.p.: 63.1−64.0 °C. HRMS: m/z (DART) calcd for

1.2 Hz, 1H), 7.35−7.23 (m, 9H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.3, 158.8, 153.7, 152.8, 138.4, 136.1, 134.7, 132.6, 132.3, 129.6, 129.4, 128.6, 128.5, 128.5, 128.0, 126.7, 126.1, 124.6, 119.4, 117.2, 21.2. HRMS: m/z (DART) calcd for C23H17O3 (M + H)+ 341.1172, found 341.1168. 3-(4-Methylbenzoyl)-6-methyl-4-phenyl-2H-chromen-2-one (3ba). Purification by flash chromatography on silica gel (Rf = 0.16 in n-hexane:toluene:ethyl acetate:acetic acid = 5:5:1:0.1). 3ba was obtained as a yellow solid (24.7 mg, 70% yield, 7.0 × 10−2 mmol). 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H), 7.34−7.31 (m, 3H), 7.27−7.25 (m, 3H), 7.17−7.15 (m, 3H), 7.06 (d, J = 8.2 Hz, 1H), 2.49 (s, 3H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.0, 163.4, 159.2, 155.6, 153.2, 144.7, 134.1, 132.8, 129.4, 129.3, 129.3, 129.0, 128.6, 128.5, 122.8, 112.9, 100.8, 55.9, 21.8. (one carbon merged to others) m.p.: 194.1−195.2 °C. HRMS: m/z (DART) calcd for C24H19O3 (M + H)+ 355.1334, found 355.1327. FTIR: (ATR) 3060, 2922, 1715, 1670, 1605, 1555, 1361, 1262 cm−1. 6-Methoxy-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one (3ca). Purification by flash chromatography on silica gel (Rf = 0.35 in n-hexane:toluene:ethyl acetate:acetic acid = 5:5:1:0.1). 3ca was obtained as a yellow solid (21.5 mg, 58% yield, 5.8 × 10−2 mmol). 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.33−7.31 (m, 3H), 7.26−7.24 (m, 2H), 7.19−7.15 (m, 3H), 6.94 (d, J = 2.9 Hz, 1H), 6.81 (dd, J1 = 8.6 Hz, J2 = 2.9 Hz, 1H), 3.91 (s, 3H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.0, 163.4, 159.2, 155.6, 153.2, 144.7, 134.0, 132.8, 129.4, 129.3, 129.3, 129.2, 129.0, 128.6, 128.5, 122.8, 112.9, 112.8, 100.9, 55.9, 21.7. m.p.: 199.9−201.0 °C. HRMS: m/z (DART) calcd for C24H18O4 (M + H)+ 371.1205, found 355.1219. FTIR: (ATR) 3062, 2922, 1721, 1668, 1605, 1588, 1356, 1279, 964 cm−1. 3-Benzoyl-7-methoxy-4-phenyl-2H-chromen-2-one (3cd).12i Purification by flash chromatography on silica gel (Rf = 0.10 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3cd was obtained as a yellow solid (11.0 mg, 31% yield, 3.1 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.37−7.30 (m, 5H), 7.26−7.24 (m, 2H), 7.18 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.9 Hz, 1H), 6.81 (dd, J = 8.6, 2.9 Hz, 1H), 3.91 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 192.5, 163.5, 159.2, 155.6, 153.5, 136.5, 133.6, 132.7, 129.4, 129.2, 129.0, 128.6, 128.5, 122.6, 112.9, 112.8, 100.9, 55.9. HRMS: m/z (DART) calcd for C23H16O4 (M + H)+ 357.1121, found 357.1122. 6-Iodo-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one (3da). Purification by flash chromatography on silica gel (Rf = 0.25 in nhexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3da was obtained as a yellow solid (16.8 mg, 36% yield, 3.6 × 10−2 mmol). 1 H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 1.5 Hz, 1H), 7.68 (d, J = 8.2 Hz, 2H), 7.57 (dd, J = 8.2, 1.5 Hz, 1H), 7.35−7.33 (m, 3H), 7.25− 7.23 (m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 6.97 (d, J = 8.2 Hz, 1H), 2.36 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.3, 158.0, 153.4, 152.2, 145.1, 133.9, 133.6, 131.9, 129.6, 129.4, 128.8, 128.7, 128.6, 126.6, 126.2, 119.0, 98.5, 21.8. (one carbon merged to others) m.p.: 219.9− 221.2 °C. HRMS: m/z (DART) calcd for C23H16O3I (M + H)+ 467.0139, found 467.0156. FTIR: (ATR) 3325, 2964, 2916, 2848, 1714, 1665, 1603, 1552, 1372, 1209, 1029 cm−1. 6-Acetoxy-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one (3ea). Purification by flash chromatography on silica gel (Rf = 0.37 in n-hexane:toluene:ethyl acetate:acetic acid = 7:7:1:0.1). 3ea was obtained as a white solid (31.4 mg, 79% yield, 7.9 × 10−2 mmol). 1 H NMR (500 MHz, CDCl3) δ 7.69 (d, J = 8.6 Hz, 2H), 7.34−7.33 (m, 3H), 7.29 (d, J = 8.6 Hz, 1H), 7.26−7.24 (m, 3H),7.17 (d, J = 8.0 Hz, 2H), 7.01 (dd, J = 2.3 Hz, 1H), 2.36 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 191.4, 168.7, 158.6, 154.2, 153.6, 152.3, 145.0, 133.7, 132.2, 129.5, 129.4, 129.4, 128.8, 128.6, 125.5, 118.6, 117.3, 110.6, 21.7, 21.1. (one carbon merged to others) m.p.: 198.2−198.6 °C. HRMS: m/z (DART) calcd for C25H18O5 (M + H)+ 399.1154, found 399.1160. FTIR: (ATR) 3061, 2916, 2857, 1767, 1718, 1670, 1605, 1563, 1361, 1280, 1195 cm−1. 6-Acetyl-3-(4-methylbenzoyl)-4-phenyl-2H-chromen-2-one (3fa). Purification by flash chromatography on silica gel (Rf = 0.37 in nhexane:toluene:ethyl acetate:acetic acid = 5:5:1:0.1). 3fa was obtained 1994

DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996

Article

The Journal of Organic Chemistry C24H19O3 (M + H)+ 355.1334, found 355.1325. FTIR: (ATR) 3061, 2924, 1716, 1670, 1604, 1571, 1353, 1263 cm−1. 3-(4-Methylbenzoyl)-7-methyl-4-phenyl-2H-chromen-2-one (3ja′). Purification by flash chromatography on silica gel (Rf = 0.14 in n-hexane:toluene:ethyl acetate:acetic acid = 15:15:1:0.3). 3ja′ was obtained as a white solid (15.8 mg, 45% yield, 4.5 × 10−2 mmol). 1H NMR (500 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 2H), 7.42 (dd, J = 8.6, 1.7 Hz, 1H), 7.37−7.33 (m, 4H), 7.27−7.26 (m, 2H), 7.16 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 2.36 (s, 3H), 2.32 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 191.8, 159.0, 152.7, 151.9, 144.8, 134.4, 133.8, 133.6, 132.5, 129.4, 129.3, 129.3, 128.7, 128.5, 127.5, 126.1, 119.1, 116.9, 21.8, 20.9. m.p.: 175.7−176.9 °C. HRMS: m/z (DART) calcd for C24H19O3 (M + H)+ 355.1334, found 355.1335. FTIR: (ATR) 3058, 2923, 1714, 1670, 1604, 1566, 1361, 1268 cm−1. Radical Trapping Experiments. Following the general procedure, except TEMPO (46.9 mg, 0.30 mmol) was added, the reaction of 1a (22.7 mg, 0.10 mmol) and 2a (118.0 μL, 1.0 mmol) for 20 h afforded 2,2,6,6-tetramethylpiperidin-1-yl 4-methylbenzoate (5) as a colorless oil (3.1 mg) after flash chromatography. An adduct of aldehyde with radical scavenger was detected as shown in Figure S1 (Supporting Information). 1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 8.6 Hz, 2H), 7.25−7.27 (m, 2H), 2.42 (s, 3H), 1.57−1.81 (m, 5H), 1.44−1.48 (m, 1H), 1.27 (s, 6H), 1.11 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 166.5, 143.5, 129.6, 129.1, 126.9, 60.4, 39.0, 31.9, 21.7, 20.8, 17.0. Cell Culture Experiment. CWR22Rv1 cells were obtained from American Type Culture Collection (Manassas, VA) and grown in RPMI medium supplemented with 5% fetal bovine serum, penicillin (100 U/mL), and streptomycin (100 μg/mL) at 37 °C in a humidified incubator containing 5% CO2. Reverse Transcription and Quantitative PCR (qPCR). Total RNA was isolated from the cells using the TRI reagent (Cosmo Bio, Tokyo, Japan), and reverse transcription was performed using a ReverTra Ace qPCR RT kit (TOYOBO, Osaka, Japan) according to the manufacturer’s instructions. qPCR was performed on a TaKaRa Thermal Cycler Dice Real-Time PCR System (Takara Bio Inc., Otsu, Japan) using the KOD SYBR qPCR Mix (TOYOBO). Expression levels of PSA mRNA in the cells were normalized relative to that of βactin using 5′-CCTCCTGAAGAATCGATTCCT-3′ and 5′GAGGTCCACACACTGAAGTT-3′ for PSA and 5′-CAAGAGATGGCCGCTGCT-3′ and 5′-TCCTTCTGCATCCTGTCGGCA-3′ for β-actin as a primer set, which served as an internal control using the 2-ΔΔCt-method.21 Cell Growth Assay. The cells were plated into a 96-well microplate at a density of 3 × 103 cells/well into phenol-red deficient RPMI medium supplemented with 5% charcoal-stripped FBS plus antibiotics. The cells were then treated for 72 h with compounds or DMSO. The number of viable CWR22Rv1 cells was measured by the MTT method using 2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium.22 Data are expressed as means ± SD of at least three independent experiments. Statistical Analysis. Data are expressed as the means ± SD of at least three independent experiments, unless otherwise noted. Statistical evaluation of the data was performed by using the unpaired Student’s t test and ANOVA, followed by Fisher’s test.

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ORCID

Eiji Yamaguchi: 0000-0002-1167-8832 Satoshi Endo: 0000-0003-0578-9672 Norihiro Tada: 0000-0003-2871-5406 Akira Ikari: 0000-0003-2696-0897 Akichika Itoh: 0000-0003-3769-7406 Notes

The authors declare no competing financial interest.

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(1) (a) Ruan, B.-F.; Cheng, H.-J.; Ren, J.; Li, H.-L.; Guo, L.-L.; Zhang, X.-X.; Liao, C. Eur. J. Med. Chem. 2015, 103, 185. (b) Sandhu, S.; Bansal, Y.; Silakari, O.; Bansal, G. Bioorg. Med. Chem. 2014, 22, 3806. (c) Carradori, S.; Secci, D.; Bolasco, A.; Chimenti, P.; D’Ascenzio, M. Expert Opin. Ther. Pat. 2012, 22, 759. (2) (a) Suparji, N. S.; Chan, G.; Sapili, H.; Arshad, N. M.; In, L. L. A.; Awang, K.; Nagoor, N. H. PLoS One 2016, 11, e0151472. (b) Á lvarezDelgado, C.; Reyes-Chilpa, R.; Estrada-Muñ iz, E.; MendozaRodríguez, C. A.; Quintero-Ruiz, A.; Solano, J.; Cerbón, M. A. J. Biochem. Mol. Toxicol. 2009, 23, 263. (3) (a) Yeggoni, D. P. R.; Manidhar, D. M.; Reddy, C. S.; Subramanyam, R. J. Biomol. Struct. Dyn. 2016, 34, 2023. (b) Sashidhara, K. V.; Modukuri, R. K.; Jadiya, P.; Rao, K. B.; Sharma, T.; Haque, R.; Singh, D. K.; Banerjee, D.; Siddiqi, M. I.; Nazir, A. ACS Med. Chem. Lett. 2014, 5, 1099. (4) (a) Singh, L. R.; Avula, S. R.; Raj, S.; Srivastava, A.; Palnati, G. R.; Tripathi, C. K. M.; Pasupuleti, M.; Sashidhara, K. V. J. Antibiot. 2017, 70, 954. (b) Klenkar, J.; Molnar, M. J. Chem. Pharm. Res. 2015, 7, 1223. (c) Thakur, A.; Singla, R.; Jaitak, V. Eur. J. Med. Chem. 2015, 101, 476. (5) (a) Liao, Y.-C.; Venkatesan, P.; Wei, L.-F.; Wu, S.-P. Sens. Actuators, B 2016, 232, 732. (b) Li, J.; Zhang, C.-F.; Yang, S.-H.; Yang, W.-C.; Yang, G.-F. Anal. Chem. 2014, 86, 3037. (c) Dai, X.; Wu, Q.-H.; Wang, P.-C.; Tian, J.; Xu, Y.; Wang, S.-Q.; Miao, J.-Y.; Zhao, B.-X. Biosens. Bioelectron. 2014, 59, 35. (d) Long, L.; Zhou, L.; Wang, L.; Meng, S.; Gong, A.; Du, F.; Zhang, C. Org. Biomol. Chem. 2013, 11, 8214. (6) (a) Su, C.; Chen, Z.-C.; Zheng, Q.-G. Synthesis 2003, 2003, 0555. (b) Song, A.; Wang, X.; Lam, K. S. Tetrahedron Lett. 2003, 44, 1755. (c) Bogdol, D. J. Chem. Res., Synop. 1998, 468. (d) Crawford, M.; Shaw, J. A. M. J. Chem. Soc. 1953, 0, 3435. (7) (a) De, S. K.; Gibbs, R. A. Synthesis 2005, 1231. (b) Garazd, M. M.; Garazd, Y. L.; Khilya, V. P. Chem. Nat. Compd. 2005, 41, 245. (c) Potdar, M. K.; Mohile, S. S.; Salunkhe, M. M. Tetrahedron Lett. 2001, 42, 9285. (d) Sethna, S.; Phadke, R. Org. React. 1953, 7, 1. (8) (a) de A. Fernandes, T.; Vaz, B. G.; Eberlin, M. N.; de Silva, A. J. M.; Costa, P. R. R. J. Org. Chem. 2010, 75, 7085. (b) Giguére, D.; Patnam, R.; Juarez-Ruiz, J. M.; Neault, M.; Roy, R. Tetrahedron Lett. 2009, 50, 4254. (c) Fernandes, T. A.; Carvalho, R. C. C.; Goncalves, T. M. D.; da Silva, A. J. M.; Costa, P. R. R. Tetrahedron Lett. 2008, 49, 3322. (d) Ulgheri, F.; Marchetti, M.; Piccolo, O. J. Org. Chem. 2007, 72, 6056. (e) Battistuzzi, G.; Cacchi, S.; De Salve, I.; Fabrizi, G.; Parisi, L. M. Adv. Synth. Catal. 2005, 347, 308. (9) (a) Hwang, I.-T.; Lee, S.-A.; Hwang, J.-S.; Lee, L.-I. Molecules 2011, 16, 6313. (b) Dittmer, D. C.; Li, Q.; Avilov, D. V. J. Org. Chem. 2005, 70, 4682. (c) Hong, H.; Neamati, N.; Wang, S.; Nicklaus, M. C.; Mazumder, A.; Zhao, H.; Burke, T. R., Jr.; Pommier, Y.; Milne, G. W. A. J. Med. Chem. 1997, 40, 930. (d) Shah, D. N.; Shah, N. M. J. Am. Chem. Soc. 1955, 77, 1699. (e) v. Kostanecki, St.; Rózẏ cki, A. Ber. Dtsch. Chem. Ges. 1901, 34, 102. (10) (a) Belavagi, N. S.; Deshapande, N.; Sunagar, M. G.; Khazi, I. A. M. RSC Adv. 2014, 4, 39667. (b) Yavari, I.; Hekmat-Shoar, R.; Zonouzi, A. Tetrahedron Lett. 1998, 39, 2391. (c) Harayama, T.; Nakatsuka, K.; nishioka, H.; Murakami, K.; Hayashida, N.; Ishii, H. Chem. Pharm. Bull. 1994, 42, 2170. (d) Liu, Y.-Y.; Thom, E.; Liebman, A. A. J. Heterocycl. Chem. 1979, 16, 799. (e) Narasimhan, N. S.; Mali, F. S.; Barve, M. V. Synthesis 1979, 1979, 906.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02933. Copies of 1H and 13C NMR spectra of all pure products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (E.Y.). *E-mail: [email protected] (A.I.). 1995

DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996

Article

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DOI: 10.1021/acs.joc.7b02933 J. Org. Chem. 2018, 83, 1988−1996