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Cite This: J. Org. Chem. 2018, 83, 13335−13343

I2‑Mediated Iodobenzannulation of Yne-Allenones toward 1‑Naphthols and Their Synthetic Application Heng Li,†,§ Peng Zhou,†,§ Feng Xie,‡ Jian-Qiang Hu,‡ Shi-Zhao Yang,‡ You-Jian Wang,*,† Wen-Juan Hao,† Shu-Jiang Tu,*,† and Bo Jiang*,† †

J. Org. Chem. 2018.83:13335-13343. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/02/18. For personal use only.

School of Chemistry & Materials Science, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, P. R. China ‡ Department of Quartermaster and Fuel, Air Force Logistic College, Xuzhou, 221000, China S Supporting Information *

ABSTRACT: A new I2-mediated iodobenzannulation of yne-allenones has been established, enabling breaking/rearranging of CC bonds to selectively access 4-iodonaphthalen-1-ols with generally good yields. The resulting 4iodonaphthalen-1-ols could serve as a new and reliable coupling reagent, which further reacted with H2O under the oxygen conditions to generate unexpected 1,2-carbonyls with good yields through Pd-catalyzed deiodinated carbonylation, whereas employment of benzene-1,2-diamine as the nucleophile rendered 3-(quinoxalin-2-yl)naphthalen-1-ols through Pd-catalyzed [4 + 2] heterocyclization. On the basis of the controlled experiments, the mechanism for forming 1,2-carbonyls was proposed, including an oxidative addition, 1,3-palladium migration, reductive elimination, and oxidative dehydrogenation sequence.

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INTRODUCTION 1-Naphthols are a valuable type of privileged structures and are the key pharmacophore commonly present in biologically active natural products,1 such as propranolol,2 korupensamine A,3 mollugin,4 and gossypol (Figure 1).5 They also have been found to display a broad spectrum of biological and medicinal properties, such as antiviral, antitumor,6 and antibacterial activity,7 among others.8 Besides, naphthols could serve as an attractive intermediate for the synthesis polycyclic structures in chemical science.9 As a consequence, considerable efforts have been focused toward developing various efficient methods for

the synthesis of such molecules.10 Most of the recent synthetic endeavors to construct this bioactive core mainly depend on the metal-catalyzed benzannulation. For examples, the groups of Wang,11a Tanaka,11b Wang,11c Narender,11d Zhu,11e. and Li11f,g independently reported transition-metal-catalyzed oxidative benzannulation of various aromatic ketone derivatives for the synthesis of polysubstituted 1-naphthols via C−H activation (Scheme 1a). In addition, the rhodium-catalyzed redox-neutral benzannulation of nitrones with cyclopropenones provided an alternative pathway to form 1-naphthols (Scheme 1b).12 However, the use of the transition metals in these procedures is generally thought not to be environmentally friendly, especially when these 1-naphthols serve as pharmaceutically active ingredients, since they are typically allowed with a low level of the heavy metal content, thereby encountering a challenging problem in the removal of heavymetal catalysts from the final products. Very recently, Wang and co-workers reported metal-free bromide-mediated intermolecular benzannulation of phenylethanones with alkynes for 1-naphthol synthesis but with the requirement of a stoichiometric amount of oxidants (Scheme 1a).13 Therefore, the development of an efficient and sustainable benzannulation for the formation of 1-naphthols without the use of metal catalysts or oxidants is of great significance. It has been well established that conjugated yne-allenones are versatile precursors for cycloaddition cascades and have

Figure 1. Several naphthol-containing natural products.

Received: August 17, 2018 Published: October 10, 2018

© 2018 American Chemical Society

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DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343

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The Journal of Organic Chemistry

reaction of N-iodosuccinimide (NIS) under our previous conditions.12 Unluckily, the expected breaking/rearranging of CC bonds toward diiodinated 1-naphthol 2a′ did not occur. Instead, a complex mixture was observed. With 1.5 equiv of I2 as the iodine source, the reaction of yne-allenone 1a with H2O proceeded smoothly in acetonitrile (CH3CN) at 50 °C under the air conditions, affording 4-iodonaphthalen-1-ol 2a in 60% yield (Table 1, entry 1). This interesting result prompted us to

Scheme 1. Profiling Applications of 1-Naphthol Synthesis

Table 1. Optimization of Reaction Conditionsa,b

been extensively utilized to construct functionalized polycyclic compounds across the CC and CC bond system in a step and atom-economic fashion.14 Recently, we reported the chemoselective synthesis of dibrominated and dichlorinated 1naphthols via breaking/rearranging of carbon−carbon triple bonds of yne-allenones by using N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS) as halogen sources (Scheme 1c).15 To continue our efforts in this project and expand the molecular diversity of 1-naphthols, we found that molecular iodine could serve as an iodine source for the iodobenzannulation of yne-allenones with H2O via breaking/rearranging of carbon−carbon triple bonds, accessing a wide range of new iodinated 1-naphthols with generally good yields and high regioselectivity (Scheme 1d). Due to aryl iodides being an important class of reaction partners in modern metal-catalyzed cross-couplings, the resulting iodinated 1-naphthols as a coupling component were subjected to the reaction of H2O under the oxygen conditions, enabling Pd-catalzyed deiodinated carbonylation to give naphthalen-2-yl-1,2-diones 3 with good yields (Scheme 1e). Using benzene-1,2-diamine 4 as a replacement for H2O, the reaction afforded high yields of 3(quinoxalin-2-yl)naphthalen-1-ols 5 via Pd-catalzyed deiodinated [4 + 2] cyclization cascades (Scheme 1f). Herein, we report these attractive transformations.

entry

I2 (equiv)

solvent

temp (°C)

yield (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14c 15d

1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 2 1.2 1.1 1.0 1.1 1.1

CH3CN DCE CH3OH 1,4-dioxane THF DMF CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

50 50 50 50 50 50 60 70 40 50 50 50 50 50 50

60 N.R. 35 26 N.D. N.D. 58 52 46 44 70 76 65 62 71

a Reaction conditions: 1a (0.2 mmol), I2 (x mmol), H2O (0.3 mmol), solvent (3.0 mL), under the air conditions for 4 h. bIsolated yield based on substrate 1a. cH2O (0.2 mmol). dH2O (0.4 mmol).

identify the optimized conditions for the intramolecular benzannulation. Then, we investigated the solvent effect by using other polar solvents, such as 1,2-dichloroethane (DCE), CH3OH, 1,4-dioxane, tetrahydrofuran (THF), and N,Ndimethylformamide (DMF), showing that all these solvents have no positive effect on the yield of 2a as compared with CH3CN (entries 2−6 vs entry 1). The reaction efficiency was proven to have an evident temperature dependence. Increasing the reaction temperature led to slightly lower conversion into 2a (entries 7−8). The similar inferior outcome was observed as the reaction temperature was dropped to 40 °C (entry 9). Next, we found that the dosage of I2 imposed an important impact on the reaction yield. The use of 2.0 equiv of I2 was found to have a detrimental effect on this transformation, as a lower yield of 44% was obtained (entry 10). In contrast, lowering the I2 loading could facilitate this transformation. Decreasing the amount of I2 to 1.2 equiv provided a 70% yield of 2a (entry 11). Gratifyingly, the desired product 2a could be generated in 76% yield when 1.1 equiv of I2 was employed (entry 12). Fine-tuning the I2 loading to 1.0 equiv gave a relatively lower conversion of 1a into 2a (entry 13). Increasing or decreasing the amount of water is harmful for this transformation (entries 14−15).

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RESULTS AND DISCUSSION In our previous report, the reaction of yne-allenones with H2O in the presence of 2.0 equiv of NBS in CH3CN at 50 °C gave dibrominated 1-naphthols via breaking/rearranging of CC bonds (Scheme 1c).15 To broaden the application of this transformation, yne-allenone 1a was subjected with the 13336

DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343

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The Journal of Organic Chemistry Scheme 3. Synthesis of 1,2-Carbonyls 3a,b

With the optimized conditions in hand, the scope of iodobenzannulation was then investigated by examining various yne-allenones, and the results are depicted in Scheme 2. Diverse functionalities on the arylalkynyl moiety of yneScheme 2. Substrate Scope for Synthesis of Products 2a,b

a

Reaction conditions: All reactions were performed with 2 (0.2 mmol), PdCl2(PPh3)2 (5 mol %), H2O (0.2 mmol), Et3N (3.0 mL) at 60 °C under the O2 (1.0 atm) conditions for 5 h. bIsolated yields in parentheses based on 2.

important synthons for the synthesis of heterocycles in organic synthesis.16 4-Iodonaphthalen-1-ols 2d, 2g, and 2i were exploited as representative substrates to be subjected with this palladium catalysis, and the transformations proceeded readily to give the corresponding 1,2-dicarbonyls 3a−3c in 65%−74% yields. To further expand the synthetic application of this Pd-catalysis, the treatment of 4-iodonaphthalen-1-ols 2 with benzene-1,2-diamine 4 under the above reaction conditions allowed Pd-catalzyed deiodinated [4 + 2] heterocyclization cascades to deliver 3-(quinoxalin-2-yl)naphthalen-1-ols 5a−5f in 67%−84% yields. The results from Scheme 4 reveal that 4-iodonaphthalen-1-ols 2 bearing Scheme 4. Synthesis of Quinoxalines 5a,b

a

Reaction conditions: All reactions were performed with 1 (0.2 mmol), I2 (0.22 mmol), H2O (0.3 mmol), CH3CN (3.0 mL) at 50 °C under the air conditions for 4 h. bIsolated yields in parentheses based on 1.

allenones were first investigated in combination with H2O and I2 under these optimal conditions. Electronically rich, neutral, or poor groups at different positions of the arylalkynyl moiety (R1) would be accommodated, confirming the success of transformations, as the corresponding 4-iodonaphthalen-1-ol products 2b−2j were afforded in 57%−84% yields. A large variety of diverse functional groups, such as chloro (1b and 1c), bromo (1d), methyl (1f and 1g), methoxy (PMP = pmethoxyphenyl, 1h), ethyl (1i), and tert-butyl (1j), were all proven to be compatible with the present intramolecular benzannulation system. Moreover, yne-allenones 1k having a 1-naphthyl (1-Np) group on the alkynyl moiety was an effective candidate, delivering 4-iodonaphthalen-1-ol 2k in 67% yield. The electronic nature of substituents (R) on the internal arene ring was then evaluated, and it was found that the reaction proceeded smoothly with various functional groups, including chloro, fluoro, methyl, and methoxy, attached by either C4 or C5 of the internal arene ring, assessing the corresponding products 2l−2z with 52%−85% yields. After the successful achievement of 4-iodonaphthalen-1-ols 2, we decided to employ them as starting materials to investigate the feasibility of intramolecular Buchwald−Hartwig cross-coupling toward the expected naphtho[1,2-b]furan-5-ols (Scheme 3). Surprisingly, instead of naphtho[1,2-b]furan-5-ols, the reaction directed an unexpected Pd-catalyzed deiodinated carbonylation to access 1,2-dicarbonyls 3. This protocol provides a new and valuable pathway for forming a 1,2dicarbonyl framework due to the 1,2-dicarbonyls being

a

Reaction conditions: All reactions were performed with 2 (0.2 mmol), 4 (0.3 mmol), PdCl2(PPh3)2 (5 mol %), H2O (0.2 mmol), Et3N (3.0 mL) at 60 °C under the O2 (1.0 atm) conditions for 5 h. b Isolated yields in brackets based on 2.

electron-withdrawing, -neutral, and -donating groups at the different positions of the aroyl ring all readily participated in the current catalytic transformation. Diverse functional groups, such as fluoro, bromo, methyl, and ethyl, would be tolerated well with the present catalytic conditions. The structures of products 2, 3, and 5 were fully characterized by their NMR and HR-MS spectral analysis. In the cases of products 2a and 5e, their structures were further confirmed by X-ray diffraction analysis (see Supporting Information).17 13337

DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343

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The Journal of Organic Chemistry In order to gain reasonable insight into the Pd-catalzyed reaction mechanism, several control experiments were conducted. The preformed compound 6 was subjected to the standard conditions, but no expected product 3a was observed with the starting material 6 remaining (Scheme 5a). These

Scheme 7. Plausible Reaction Pathway for Forming 3

Scheme 5. Control Experiments

palladium complex D and the following 1,3-palladium migration and ligand exchange occur,18 giving intermediate F. Intermediate F undergoes reductive elimination to access αhydroxyketone intermediate G and regenerate the Pd(0) catalyst to complete catalytic cycles. The final product 3 is obtained via oxidative dehydrogenation. In conclusion, starting from easily available yne-allenones, we have established a new iodobenzannulation toward a range of richly decorated 4-iodonaphthalen-1-ols with generally good yields, in which I2 plays dual roles as a Lewis acid catalyst as well as a reaction partner. The combination of I2-promoted [2 + 2] cycloaddition with iodohydroxylation directly drove C C bond breaking and rearranging of yne-allenones, making the original alkyne motif split into two parts followed by remerging them into one molecular framework. The resulting 4iodonaphthalen-1-ols as a new and reliable coupling reagent was successfully applied in the synthesis of 1,2-carbonyls and 3-(quinoxalin-2-yl)naphthalen-1-ols with good yields through Pd-catalysis. The current benzannulation reaction provides an atom-economic and green strategy to synthesize 1-naphthalenols. Further investigations on the synthetic application of 4iodonaphthalen-1-ols will be conducted in due course.

results indicate that the iodo-substituent in the C4 position of phthalen-1-ol skeleton plays a key role in the success of this transformation. Without H2O, the Pd-catalysis did not work, suggesting that the oxygen of the new forming carbonyl group may come from the H2O, rather than O2 (Scheme 5b). The treatment of 2f with D2O gave the deuterated 1-naphthol [D]3b with the percentage content of deuterium being 14% at the 4-position of the 1-naphthol scaffold (Scheme 5c), showing that the proton at the C4 position comes from the α-position of the carbonyl group of substrates 2 via 1,3-palladium migration18 and the observation of the deuterium substituent may be caused by the enol-keto tautomerization of 1-naphthols with D2O through the intermolecular proton transfer. Combining the aforementioned results and our previous reports on the transformations of yne-allenones,14,15 a reasonable mechanism for the formation of product 2 was proposed as shown in Scheme 6. First, I2-promoted [2 + 2]

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Scheme 6. Plausible Reaction Pathway for Forming 2

EXPERIMENTAL SECTION

General Information. All melting points are uncorrected. The NMR spectra were recorded in CDCl3 or DMSO-d6 on a 400 MHz instrument with TMS as the internal standard. Chemical shifts (δ) were reported in ppm with respect to TMS. Data are represented as follows: chemical shift, mutiplicity (s = singlet, d = doublet, t = triplet, m = multiplet), coupling constant (J, Hz), and integration. HRMS analyses were carried out using a TOF-MS instrument with an ESI source. X-ray crystallographic analysis was performed with a SMART CCD and a P4 diffractometer. General Procedure for the Synthesis of 2. Example for the Synthesis of 2a. 1-(2-((4-Fluorophenyl)ethynyl)phenyl)buta-2,3dien-1-one (1a, 0.2 mmol, 52.4 mg), I2 (0.22 mol, 55.9 mg), H2O (0.3 mmol, 5.4 mg), and dry CH3CN (3.0 mL) were successively added in a 10 mL reaction vial. Then, the reaction vial was sealed and heated at 50 °C for 4 h until TLC (petroleum ether ethyl acetate 5:1) revealed that conversion of the starting material 1a was completed. Next, the reaction mixture was cooled to room temperature and water (10 mL) was added into the reaction system. The organic phase was collected and concentrated by vacuum distillation and was purified by flash column chromatography (silica gel, mixtures of petroleum ether/ acetic ester, 30:1, v/v) to afford the desired pure products as a white solid. 1-(4-Fluorophenyl)-2-(4-hydroxy-1-iodonaphthalen-2-yl)ethanone (2a). White solid, 61.9 mg, 76% yield; mp 191−193 °C; 1H

cycloaddition of yne-allenones generates cyclobutene intermediate A, followed by iodohydroxylation in the presence of I2 and H2O to give C. Subsequently, the ring opening of cyclobutene and hydrogen transfer yield the final products 2 (Scheme 6). A plausible mechanism for forming 3 is shown in Scheme 7. The oxidative addition of 2 to the Pd(0) catalyst generates the 13338

DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343

Article

The Journal of Organic Chemistry NMR (400 MHz, DMSO-d6; δ, ppm) 10.46 (s, 1H, OH), 8.23−8.20 (m, 2H, Ar−H), 8.15 (d, J = 8.4 Hz, 1H, Ar−H), 8.06 (d, J = 8.4 Hz, 1H, Ar−H), 7.64−7.61(m, 1H, Ar−H), 7.54−7.50(m, 1H, Ar−H), 7.45−7.40 (m, 2H, Ar−H), 6.92 (s, 1H, Ar−H), 4.78 (s, 2H, CH2). 13 C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 195.6, 166.9 (1JCF = 250.6 Hz), 154.0, 139.4, 135.5, 133.9 (4JCF = 2.8 Hz), 131.87, 131.6 (3JCF = 9.4 Hz), 128.8, 125.6, 125.1, 123.0, 116.3 (2JCF = 21.8 Hz), 112.2, 93.9, 52.4. IR (KBr, ν, cm−1) 3415, 3217, 1635, 1616, 1558, 1384, 1184, 1129, 1043, 688. HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H13FIO2 406.9944; found 406.9960. 1-(4-Chlorophenyl)-2-(4-hydroxy-1-iodonaphthalen-2-yl)ethanone (2b). White solid, 57.5 mg, 68% yield; mp 193−195 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.48 (s, 1H, OH), 8.16 (d, J = 8.0 Hz, 2H, Ar−H), 8.12 (s, 1H, Ar−H), 8.06 (d, J = 8.4 Hz, 1H, Ar− H), 7.67 (d, J = 8.4 Hz, 2H, Ar−H), 7.64−7.60 (m, 1H, Ar−H), 7.54−7.50 (m, 1H, Ar−H), 6.93 (s, 1H, Ar−H), 4.78 (s, 2H, CH2). 13 C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.1, 154.0, 139.3, 138.8, 135.8, 135.5, 131.9, 130.5, 129.5, 128.8, 125.6, 125.1, 123.0, 112.2, 93.9, 52.5. IR (KBr, ν, cm−1) 3415, 3236, 1635, 1616, 1520, 1384, 1182, 1151, 1043, 688. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H13ClIO2 422.9649; found 422.9660. 1-(2-Chlorophenyl)-2-(4-hydroxy-1-iodonaphthalen-2-yl)ethanone (2c). White solid; 53.3 mg, 63% yield; mp 176−178 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.51 (s, 1H, OH), 8.15 (d, J = 8.0 Hz, 1H, Ar−H), 8.07 (d, J = 8.4 Hz, 1H, Ar−H), 7.85 (d, J = 7.2 Hz, 1H, Ar−H), 7.57 (m, 5H, Ar−H), 6.98 (s, 1H, Ar−H), 4.69 (s, 2H, CH2). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 199.0, 154.1, 138.9, 138.4, 135.5, 132.9, 132.0, 131.1, 130.2, 129.7, 128.9, 127.9, 125.8, 125.2, 123.0, 112.1, 93.9, 56.1. IR (KBr, ν, cm−1) 3415, 3230, 1639, 1620, 1521, 1386, 1180, 1152, 1033, 682. HRMS (ESITOF) m/z [M + H]+ calcd for C18H13ClIO2 422.9649; found 422.9633. 1-(4-Bromophenyl)-2-(4-hydroxy-1-iodonaphthalen-2-yl)ethanone (2d). White solid; 58.8 mg, 62% yield; mp 194−196 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.47 (s, 1H, OH), 8.17 (d, J = 8.4 Hz, 3H, Ar−H), 8.05 (d, J = 8.4 Hz, 1H, Ar−H), 7.78 (d, J = 8.4 Hz, 2H, Ar−H), 7.68 (d, J = 8.4 Hz, 1H, Ar−H), 7.57 (d, 1H, J = 8.4 Hz, 1H, Ar−H), 6.94 (s, 1H, Ar−H), 4.81 (s, 2H, CH2). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.1, 154.0, 139.3, 136.2, 135.5, 132.4, 131.9, 130.6, 128.8, 128.0, 125.6, 125.1, 123.0, 112.2, 93.8, 52.5. IR (KBr, ν, cm−1) 3415, 3197, 1653 1617, 1558, 1384, 1184, 1129, 1043, 688. HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H13BrIO2 466.9144; found 466.9120. 2-(4-Hydroxy-1-iodonaphthalen-2-yl)-1-phenylethanone (2e). White solid; 65.4 mg, 84% yield; mp: 189−191 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.47 (s, 1H, OH), 8.16−8.11 (m, 3H, Ar− H), 8.06 (d, J = 8.4 Hz, 1H, Ar−H), 7.72−7.69 (m, 1H, Ar−H), 7.64−7.58 (m, 3H, Ar−H), 7.54−7.50 (m, 1H, Ar−H), 6.93 (s, 1H, Ar−H), 4.79 (s, 2H, CH2). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 197.0, 154.0, 139.5, 137.1, 135.5, 133.9, 131.9, 129.3, 128.8, 128.6, 125.6, 125.1, 123.0, 112.2, 93.9, 52.5. IR (KBr, ν, cm−1) 3445, 3176, 1652, 1616, 1575, 1385, 1184, 1129, 1043, 688. HRMS (ESITOF) m/z [M + H]+ calcd for C18H14IO2 389.0038; found 389.0023. 2-(4-Hydroxy-1-iodonaphthalen-2-yl)-1-(p-tolyl)ethanone (2f). White solid; 54.0 mg, 67% yield; mp 172−174 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.45 (s, 1H, OH), 8.15 (d, J = 8.4 Hz, 1H, Ar−H), 8.06 (d, J = 8.4 Hz, 1H, Ar−H), 8.01 (d, J = 8.0 Hz, 2H, Ar− H), 7.64−7.60 (m, 1H, Ar−H), 7.53−7.49 (m, 1H, Ar−H), 7.40 (d, J = 8.4 Hz, 2H, Ar−H), 6.91 (s, 1H, Ar−H), 4.74 (s, 2H, CH2), 2.41 (s, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.5, 154.0, 144.3, 139.7, 135.5, 134.7, 131.9, 129.9, 128.8, 128.7, 125.6, 125.0, 123.0, 112.2, 93.8, 52.4, 21.7. IR (KBr, ν, cm−1) 3415, 3196, 1652, 1616, 1568, 1384, 1182, 1151, 1043, 688. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H16IO2 403.0195; found 403.0188. 2-(4-Hydroxy-1-iodonaphthalen-2-yl)-1-(m-tolyl)ethanone (2g). White solid; 51.6 mg, 64% yield; mp 171−173 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.46 (s, 1H, OH), 8.15 (d, J = 8.0 Hz, 1H, Ar−H), 8.06 (d, J = 8.4 Hz, 1H, Ar−H), 7.92 (d, J = 8.4 Hz, 2H, Ar− H), 7.62 (m, 1H, Ar−H), 7.50 (m, 3H, Ar−H), 6.92 (s, 1H, Ar−H), 4.77 (s, 2H, CH2), 2.42 (s, 3H, CH3). 13C{1H} NMR (100 MHz,

DMSO-d6; δ, ppm) 197.0, 154.0, 139.6, 138.7, 137.2, 135.5, 134.5, 131.9, 129.2, 128.9, 128.8, 125.8, 125.6, 125.1, 123.0, 112.2, 93.9, 52.6, 21.4. IR (KBr, ν, cm−1) 3413, 3191, 1653, 1610, 1551, 1362, 1180, 1123, 1042, 686. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H16IO2 403.0195; found 403.0181. 2-(4-Hydroxy-1-iodonaphthalen-2-yl)-1-(4-methoxyphenyl)ethanone (2h). White solid; 61.2 mg, 73% yield; mp 162−164 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.44 (s, 1H, OH), 8.15 (d, J = 8.4 Hz, 1H, Ar−H), 8.10−8.06 (m, 3H, Ar−H), 7.64−7.60 (m, 1H, Ar−H), 7.53−7.49 (m, 1H, Ar−H), 7.10 (d, J = 8.8 Hz, 2H, Ar−H), 6.91 (s, 1H, Ar−H), 4.71 (s, 2H, CH2), 3.87 (s, 3H, OCH3). 13 C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 195.3, 163.8, 154.0, 139.8, 135.5, 131.9, 130.9, 130.0, 128.8, 125.6, 125.0, 123.0, 114.5, 112.1, 93.8, 56.1, 52.2. IR (KBr, ν, cm−1) 3416, 3217, 1653, 1617, 1558, 1384, 1220, 1182, 1043, 685. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H16IO3 419.0144; found 419.0168. 1-(4-Ethylphenyl)-2-(4-hydroxy-1-iodonaphthalen-2-yl)ethanone (2i). White solid; 62.6 mg, 75% yield; mp 165−167 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.45 (s, 1H, OH), 8.15 (d, J = 8.4 Hz, 1H, Ar−H), 8.07−8.03 (m, 3H, Ar−H), 7.64−7.60 (m, 1H, Ar−H), 7.53−7.49 (m, 1H, Ar−H), 7.43 (d, J = 8.0 Hz, 2H, Ar−H), 6.91 (s, 1H, Ar−H), 4.75 (s, 2H, CH2), 2.74−2.69(m, 2H, CH2), 1.23 (m, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.5, 154.0, 150.4, 139.7, 135.5, 134.9, 131.9, 128.8, 128.7, 125.6, 125.1, 123.0, 112.1, 93.8, 52.4, 28.7, 15.7. IR (KBr, ν, cm−1) 3415, 3216, 1668, 1617, 1558, 1385, 1183, 1129, 1043, 668. HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H18IO2 417.0351; found 417.0328. 1-(4-(tert-Butyl)phenyl)-2-(4-hydroxy-1-iodonaphthalen-2-yl)ethanone (2j). White solid; 50.7 mg, 57% yield; mp 182−184 °C; 1H NMR (400 MHz, CDCl3; δ, ppm) 8.17 (d, J = 8.4 Hz, 1H, Ar−H), 8.06 (d, J = 8.4 Hz, 2H, Ar−H), 7.91 (d, J = 8.4 Hz, 1H, Ar−H), 7.53 (d, J = 8.4 Hz, 3H, Ar−H), 7.39−7.35 (m, 1H, Ar−H), 6.75 (s, 1H, Ar−H), 4.71 (s, 2H, CH2), 1.37 (s, 9H, C4H9). 13C{1H} NMR (100 MHz, CDCl3; δ, ppm) 198.4, 157.7, 153.0, 137.3, 135.8, 133.8, 132.2, 128.8, 128.3, 125.8, 125.5, 122.4, 111.1, 95.0, 52.6, 35.2, 31.1. IR (KBr, ν, cm−1) 3415, 3170, 1656, 1620, 1552, 1382, 1178, 1152, 1047, 689. HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H22IO2 445.0664; found 445.0679. 2-(4-Hydroxy-1-iodonaphthalen-2-yl)-1-(naphthalen-1-yl)ethanone (2k). White solid; 58.8 mg, 67% yield; mp 170−172 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.50 (s, 1H, OH), 8.52 (d, J = 8.8 Hz, 1H, Ar−H), 8.36 (d, J = 7.2 Hz, 1H, Ar−H), 8.20−8.15 (m, 2H, Ar−H), 8.08−8.03 (m, 2H, Ar−H), 7.69 (s, 1H, Ar−H), 7.65− 7.61 (m, 3H, Ar−H), 7.53 (d, J = 7.6 Hz, 1H, Ar−H), 7.05 (s, 1H, Ar−H), 4.88 (s, 2H, CH2). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 200.8, 154.1, 139.6, 135.7, 135.6, 134.0, 133.2, 131.9, 129.9, 129.0, 128.9, 128.7, 128.3, 126.9, 125.8, 125.3, 123.0, 112.1, 94.0, 55.6. IR (KBr, ν, cm−1) 3415, 2964, 1636, 1617, 1558, 1385, 1184, 1043, 668. HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H16IO2 439.0195; found 439.0196. 2-(6-Chloro-4-hydroxy-1-iodonaphthalen-2-yl)-1-(4chlorophenyl)ethanone (2l). White solid; 74.9 mg, 82% yield; mp 196−198 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.69 (s, 1H, OH), 8.13 (d, J = 8.0 Hz, 3H, Ar−H), 8.09 (d, J = 8.8 Hz, 1H, Ar− H), 7.67 (d, J = 8.0 Hz, 2H, Ar−H), 7.63 (d, J = 9.2 Hz, 1H, Ar−H), 6.97 (s, 1H, Ar−H), 4.78 (s, 2H, CH2). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 195.9, 153.2, 140.2, 138.9, 135.7, 134.4, 134.0, 130.6, 130.5, 129.5, 129.1, 125.4, 121.6, 113.3, 93.4, 52.4. IR (KBr, ν, cm−1) 3414, 3236, 1636, 1616, 1384, 1157, 1041, 617. HRMS (ESITOF) m/z [M + H]+ calcd for C18H12Cl2IO2 456.9259; found 456.9265. 2-(6-Chloro-4-hydroxy-1-iodonaphthalen-2-yl)-1-phenylethanone (2m). White solid; 66.0 mg, 78% yield; mp 192−194 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.70 (s, 1H, OH), 8.14−8.08 (m, 4H, Ar−H), 7.73−7.69 (m, 1H, Ar−H), 7.65−7.58 (m, 3H, Ar− H), 6.97 (s, 1H, Ar−H), 4.80 (s, 2H, CH2). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.8, 153.2, 140.4, 137.1, 134.4, 134.1, 134.0, 130.6, 129.3, 129.1, 128.6, 125.4, 121.6, 113.3, 93.4, 52.4. IR (KBr, ν, cm−1) 3413, 3218, 1636, 1616, 1557, 1384, 1185, 1129, 13339

DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343

Article

The Journal of Organic Chemistry 1042, 617. HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H13ClIO2 422.9649; found 422.9629. 2-(6-Chloro-4-hydroxy-1-iodonaphthalen-2-yl)-1-(p-tolyl)ethanone (2n). White solid; 69.0 mg, 79% yield; mp 187−189 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.70 (s, 1H, OH), 8.13 (d, J = 2.0 Hz, 1H, Ar−H), 8.09 (d, J = 9.2 Hz, 1H, Ar−H), 8.01 (d, J = 8.0 Hz, 2H, Ar−H), 7.65−7.62 (m, 1H, Ar−H), 7.40 (d, J = 8.0 Hz, 2H, Ar−H), 6.96 (s, 1H, Ar−H), 4.75 (s, 2H, CH2), 2.41 (s, 3H, CH3). 13 C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.3, 153.1, 144.4, 140.5, 134.6, 134.4, 134.0, 130.6, 129.9, 129.0, 128.7, 125.4, 121.6, 113.2, 93.4, 52.3, 21.7. IR (KBr, ν, cm−1) 3415, 3236, 1637, 1616, 1384, 1185, 1151,1129, 1042, 618. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15ClIO2 436.9796; found 436.9805. 2-(6-Chloro-4-hydroxy-1-iodonaphthalen-2-yl)-1-(4-methoxyphenyl)ethanone (2o). White solid; 50.7 mg, 56% yield; mp 177− 179 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.69 (s, 1H, OH), 8.13 (d, J = 2.0 Hz, 1H, Ar−H), 8.09 (d, J = 8.4 Hz, 3H, Ar−H), 7.63 (m, 1H, Ar−H), 7.10 (d, J = 8.8 Hz, 2H, Ar−H), 6.94 (s, 1H, Ar−H), 4.72 (s, 2H, CH2), 3.87 (s, 3H, OCH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 195.2, 163.8, 153.1, 140.7, 134.4, 134.0, 130.9, 130.6, 130.0, 129.0, 125.4, 121.6, 114.5, 113.2, 93.4, 56.1, 52.1. IR (KBr, ν, cm−1) 3420, 3180, 1665, 1642, 1530, 1358, 1162, 1131, 1010, 699. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15ClIO3 452.9754; found 452.9756. 1-(4-(tert-Butyl)phenyl)-2-(6-chloro-4-hydroxy-1-iodonaphthalen-2-yl)ethanone (2p). White solid; 76.6 mg, 80% yield; mp 185−187 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.70 (s, 1H, OH), 8.13 (d, J = 2.4 Hz, 1H, Ar−H), 8.09 (d, J = 9.2 Hz, 1H, Ar−H), 8.05 (d, J = 8.4 Hz, 2H, Ar−H), 7.65−7.58 (m, 3H, Ar−H), 6.96 (s, 1H, Ar−H), 4.76 (s, 2H, CH2), 1.33 (s, 9H, C4H9). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.3, 157.0, 153.1, 140.5, 134.5, 134.4, 134.1, 130.6, 129.0, 128.6, 126.1, 125.4, 121.6, 113.2, 93.4, 52.3, 35.4, 31.3. IR (KBr, ν, cm−1) 3413, 3236, 1636, 1616, 1538, 1558, 1364, 1217, 1079, 617. HRMS (ESI-TOF) m/z [M + H]+ calcd for C22H21ClIO2 479.0275; found 479.0264. 2-(6-Fluoro-4-hydroxy-1-iodonaphthalen-2-yl)-1-phenylethanone (2q). White solid; 48.0 mg, 59% yield; mp 150−152 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.61 (s, 1H, OH), 8.20−8.07 (m, 3H, Ar−H), 7.81 (m, 1H, Ar−H), 7.70 (m, 1H, Ar−H), 7.60 (m, 2H, Ar−H), 7.55−7.50 (m, 1H, Ar−H), 6.95 (s, 1H, Ar−H), 4.79 (s, 2H, CH2). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.9, 161.4 (1JCF = 242.3 Hz), 153.4, 139.1 (4JCF = 2.5 Hz), 137.1, 135.2, 133.9, 132.7, 129.3, 128.6, 125.4 (3JCF = 8.5 Hz), 118.6, 112.9, 106.8, 106.4 (2JCF = 21.7 Hz), 93.4, 52.4. IR (KBr, ν, cm−1) 3422, 3176, 1679, 1575, 1322, 1100, 1040, 976, 901, 722. HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H13FIO2 406.9944; found 406.9949. 2-(6-Fluoro-4-hydroxy-1-iodonaphthalen-2-yl)-1-(p-tolyl)ethanone (2r). White solid; 47.1 mg, 56% yield; mp 155−157 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.59 (s, 1H, OH), 8.14 (m, 1H, Ar−H), 8.01 (d, J = 8.0 Hz, 2H, Ar−H), 7.80 (m, 1H, Ar−H), 7.53 (m, 1H, Ar−H), 7.39 (d, J = 8.0 Hz, 2H, Ar−H), 6.93 (s, 1H, Ar−H), 4.74 (s, 2H, CH2), 2.41 (s, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.4, 160.2 (1JCF = 242.7 Hz), 153.4, 144.3, 139.2 (6JCF = 2.4 Hz), 135.2 (4JCF = 8.8 Hz), 134.6, 132.8, 129.9, 128.7, 125.4 (5JCF = 8.6 Hz), 118.5 (2JCF = 24.8 Hz), 112.8, 106.3 (3JCF = 22.2 Hz), 93.4, 52.2, 21.7. IR (KBr, ν, cm−1) 3422, 3176, 1679, 1575, 1322, 1100, 1040, 976, 901, 722. HRMS (ESITOF) m/z [M + H]+ calcd for C19H15FIO2 421.0101; found 421.0109. 1-(4-Fluorophenyl)-2-(4-hydroxy-1-iodo-6-methoxynaphthalen2-yl)ethanone (2s). White solid; 74.3 mg, 85% yield; mp 186−188 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.37 (s, 1H, OH), 8.22−8.18 (m, 2H, Ar−H), 7.98 (d, J = 9.2 Hz, 1H, Ar−H), 7.48 (d, J = 2.8 Hz, 1H, Ar−H), 7.44−7.40 (m, 2H, Ar−H), 7.28−7.25 (m, 1H, Ar−H), 6.87 (s, 1H, Ar−H), 4.72 (s, 2H, CH2), 3.90 (s, 3H, OCH3). 13 C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 195.8, 159.0 (1JCF = 254.2 Hz), 157.3, 153.0, 136.6, 133.9 (4JCF = 2.9 Hz), 133.7, 131.6 (3JCF = 9.3 Hz), 130.9, 125.8, 120.8, 116.3 (2JCF = 21.8 Hz), 112.4, 101.3, 93.6, 55.8, 52.1. IR (KBr, ν, cm−1) 3415, 3217, 1636, 1617,

1507, 1385, 1184, 1042, 668. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15FIO3 437.0050; found 437.0071. 1-(4-Bromophenyl)-2-(4-hydroxy-1-iodo-6-methoxynaphthalen2-yl)ethanone (2t). White solid; 69.6 mg, 70% yield; mp 188−190 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.36 (s, 1H, OH), 8.60 (d, J = 4.0 Hz, 1H, Ar−H), 8.04 (d, J = 8.4 Hz, 1H, Ar−H), 7.97 (d, J = 9.6 Hz, 1H, Ar−H), 7.81 (d, J = 8.4 Hz, 2H, Ar−H), 7.48 (d, J = 2.8 Hz, 1H, Ar−H), 7.26 (m, 1H, Ar−H), 6.87 (s, 1H, Ar−H), 4.71 (s, 2H, CH2), 3.90 (s, 3H, OCH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.5, 157.3, 153.0, 136.6, 136.3, 133.7, 132.4, 130.9, 130.7, 128.0, 120.8, 112.4, 101.2, 93.6, 55.8, 52.1. IR (KBr, ν, cm−1) 3452, 3106, 1675, 1615, 1320, 1202, 1046, 1006, 921, 672. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15BrIO3 496.9249; found 496.9268. 2-(4-Hydroxy-1-iodo-6-methoxynaphthalen-2-yl)-1-phenylethanone (2u). White solid; 61.2 mg, 73% yield; mp 176−178 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.35 (s, 1H, OH), 8.11 (d, J = 8.0 Hz, 2H, Ar−H), 7.98 (d, J = 9.2 Hz, 1H, Ar−H), 7.72−7.68 (m, 1H, Ar−H), 7.61−7.57 (m, 2H, Ar−H), 7.48 (d, J = 2.4 Hz, 1H, Ar− H), 7.28−7.25 (m, 1H, Ar−H), 6.88 (s, 1H, Ar−H), 4.73 (s, 2H, CH2), 3.91 (s, 3H, OCH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 197.1, 157.3, 153.0, 137.1, 136.7, 133.9, 133.8, 130.9, 129.3, 128.6, 125.8, 120.8, 112.4, 101.2, 93.6, 55.8, 52.2. IR (KBr, ν, cm−1) 3414, 3217, 1636, 1616, 1540 1385, 1184, 1042, 668. HRMS (ESITOF) m/z [M + H]+ calcd for C19H16IO3 419.0144; found 419.0154. 2-(4-Hydroxy-1-iodo-6-methoxynaphthalen-2-yl)-1-(p-tolyl)ethanone (2v). White solid; 57.2 mg, 66% yield; mp 184−186 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.30 (s, 1H, OH), 8.01−7.97 (m, 3H, Ar−H), 7.48 (d, J = 1.6 Hz, 1H, Ar−H), 7.39 (d, J = 8.0 Hz, 2H, Ar−H), 7.26 (d, J = 9.2 Hz, 1H, Ar−H), 6.87 (s, 1H, Ar−H), 4.68 (s, 2H, CH2), 3.91 (s, 3H, OCH3), 2.41 (s, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.7, 157.3, 152.9, 144.3, 136.8, 134.7, 133.8, 130.9, 129.8, 128.7, 125.8, 120.7, 112.4, 101.2, 93.5, 55.8, 52.1, 21.7. IR (KBr, ν, cm−1) 3415, 3217, 1636, 1617, 1558, 1385, 1183, 1043, 668. HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H18IO3 433.0301; found 433.0321. 1-(4-Chlorophenyl)-2-(4-hydroxy-1-iodo-7-methylnaphthalen-2yl)ethanone (2w). White solid; 49.8 mg, 52% yield; mp 185−187 °C; 1 H NMR (400 MHz, DMSO-d6; δ, ppm) 10.38 (s, 1H, OH), 8.13 (d, J = 8.4 Hz, 2H, Ar−H), 8.05 (d, J = 8.4 Hz, 1H, Ar−H), 7.83 (s, 1H, Ar−H), 7.66 (d, J = 8.4 Hz, 2H, Ar−H), 7.35 (d, J = 8.4 Hz, 1H, Ar− H), 6.85 (s, 1H, Ar−H), 4.75 (s, 2H, CH2), 2.52 (s, 3H, CH3). 13 C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.1, 154.0, 139.3, 138.8, 138.2, 135.8, 135.7, 130.9, 130.5, 129.4, 127.6, 123.3, 123.1, 111.5, 93.2, 52.5, 22.0. IR (KBr, ν, cm−1) 3422, 3150, 1665, 1619, 1511, 1332, 1149, 1100, 1010, 688. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15ClIO2 436.9805; found 436.9826. 2-(4-Hydroxy-1-iodo-7-methylnaphthalen-2-yl)-1-phenylethanone (2x). White solid; 53.2 mg, 65% yield; mp 178−180 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.37 (s, 1H, OH), 8.11 (d, J = 7.6 Hz, 2H, Ar−H), 8.05 (d, J = 8.4 Hz, 1H, Ar−H), 7.84 (s, 1H, Ar− H), 7.70 (m, 1H, Ar−H), 7.59 (m, 2H, Ar−H), 7.35 (d, J = 8.4 Hz, 1H, Ar−H), 6.86 (s, 1H, Ar−H), 4.76 (s, 2H, CH2), 2.53 (s, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 197.0, 154.0, 139.5, 138.2, 137.1, 135.7, 133.9, 130.9, 129.3, 128.6, 127.6, 123.3, 123.1, 111.5, 93.2, 52.5, 22.0. IR (KBr, ν, cm−1) 3422, 3150, 1675, 1609, 1505, 1316, 1142, 1101, 974, 683. HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H16IO2 403.0195; found 403.0204. 2-(4-Hydroxy-1-iodo-7-methylnaphthalen-2-yl)-1-(p-tolyl)ethanone (2y). White solid; 55.9 mg, 67% yield; mp 175−177 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.37 (s, 1H, OH), 8.02 (m, 3H, Ar−H), 7.83 (s, 1H, Ar−H), 7.39 (d, J = 8.0 Hz, 2H, Ar−H), 7.34 (m, 1H, Ar−H), 6.84 (s, 1H, Ar−H), 4.71 (s, 2H, CH2), 2.52 (s, 3H, CH3), 2.41 (s, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.5, 154.0, 144.3, 139.6, 138.2, 135.7, 134.7, 130.9, 129.8, 128.7, 127.6, 123.6, 123.1, 111.5, 93.2, 52.4, 22.0, 21.7. IR (KBr, ν, cm−1) 3429, 3110, 1677, 1654, 1450, 1212, 1102, 1070, 961, 672. HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H18IO2 417.0135; found 417.0125. 13340

DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343

Article

The Journal of Organic Chemistry

concentrated by vacuum distillation, which was purified by flash column chromatography (silica gel, mixtures of petroleum ether/ acetic ester, 10:1, v/v) to afford the desired pure product 5a as a yellow solid. 3-(3-(4-Fluorophenyl)quinoxalin-2-yl)naphthalen-1-ol (5a). Yellow solid; 54.9 mg, 75% yield; mp 181−183 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.30 (s, 1H, OH), 8.19 (m, 2H, Ar−H), 8.13 (m, 1H, Ar−H), 7.91 (m, 2H, Ar−H), 7.76 (m, 1H, Ar−H), 7.60 (m, 2H, Ar−H), 7.54−7.44 (m, 3H, Ar−H), 7.21 (m, 2H, Ar−H), 7.03 (s, 1H, Ar−H). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 162.8 (1JCF = 244.9 Hz), 153.5, 153.4, 152.5, 140.9, 140.8, 137.1, 135.7 (4JCF = 3.1 Hz), 134.2, 132.4 (3JCF = 8.6 Hz), 131.0, 130.9, 129.3, 129.2, 128.5, 127.2, 126.1, 124.9, 122.4, 120.9, 115.7 (2JCF = 21.6 Hz), 109.5. IR (KBr, ν, cm−1) 3399, 3052, 1506, 1443, 1332, 1227, 1103, 1062, 991, 883, 758. HRMS (ESI-TOF) m/z [M − H]− calcd for C 24H 14 FN 2O 365.1090; found 365.1081. Chemical formula: C24H15FN2O. 3-(3-(4-Bromophenyl)quinoxalin-2-yl)naphthalen-1-ol (5b). Yellow solid; 57.1 mg, 67% yield; mp 164−166 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.31 (s, 1H, OH), 8.23−8.16 (m, 2H, Ar−H), 8.13 (m, 1H, Ar−H), 7.95−7.89 (m, 2H, Ar−H), 7.78 (m, 1H, Ar− H), 7.57 (d, J = 8.4 Hz, 2H, Ar−H), 7.54−7.47 (m, 5H, Ar−H), 7.02 (s, 1H, Ar−H). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 153.5, 153.4, 152.3, 141.0, 140.9, 138.5, 137.0, 134.3, 132.2, 131.6, 131.1, 131.0, 129.3, 128.6, 127.2, 126.2, 124.9, 123.0, 122.4, 120.9, 109.5. IR (KBr, ν, cm−1) 3406, 3055, 1516, 1446, 1322, 1218, 1102, 1052, 971, 892, 778. HRMS (ESI-TOF) m/z [M − H]− calcd for C24H14BrN2O 425.0290; found 425.0298. 3-(3-Phenylquinoxalin-2-yl)naphthalen-1-ol (5c). Yellow solid; 56.4 mg, 81% yield; mp 247−249 °C; 1H NMR (400 MHz, DMSOd6; δ, ppm) 10.28 (s, 1H, OH), 8.19 (m, 2H, Ar−H), 8.15−8.09 (m, 1H, Ar−H), 7.90 (m, 2H, Ar−H), 7.74−7.68 (m, 1H, Ar−H), 7.56 (d, J = 6.8 Hz, 2H, Ar−H), 7.47 (m, 3H, Ar−H), 7.37 (m, 3H, Ar− H), 7.07 (s, 1H, Ar−H). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 153.6, 153.5, 153.4, 140.9, 139.3, 137.3, 134.2, 130.9, 130.1, 129.3, 129.2, 128.6, 128.5, 127.1, 126.1, 124.9, 122.4, 120.9, 109.5. IR (KBr, ν, cm−1) 3409, 3049, 1510, 1456, 1308, 1212, 1100, 1032, 972, 896, 774. HRMS (ESI-TOF) m/z [M − H]− calcd for C24H15N2O 347.1185; found 347.1199. 3-(3-(p-Tolyl)quinoxalin-2-yl)naphthalen-1-ol (5d). Yellow solid; 56.5 mg, 78% yield; mp 230−232 °C; 1H NMR (400 MHz, DMSOd6; δ, ppm) 10.27 (s, 1H, OH), 8.17 (m, 2H, Ar−H), 8.12 (m, 1H, Ar−H), 7.89 (m, 2H, Ar−H), 7.76 (m, 1H, Ar−H), 7.48 (m, 5H), 7.16 (d, J = 8.0 Hz, 2H, Ar−H), 7.02 (s, 1H, Ar−H), 2.30 (s, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 153.6, 153.4, 153.0, 140.9, 140.8, 138.9, 137.6, 136.4, 134.2, 130.8, 130.7, 130.0, 129.2, 129.1, 128.5, 127.2, 126.1, 124.9, 122.4, 120.7, 109.5, 21.3. IR (KBr, ν, cm−1) 3414, 3043, 1500, 1436, 1302, 1211, 1104, 1022, 971, 892, 773. HRMS (ESI-TOF) m/z [M − H]− calcd for C25H17N2O 361.1341; found 361.1339. 3-(3-(m-Tolyl)quinoxalin-2-yl)naphthalen-1-ol (5e). Yellow solid; 52.1 mg, 72% yield; mp 237−239 °C; 1H NMR (400 MHz, DMSOd6; δ, ppm) 10.27 (s, 1H, OH), 8.25−8.15 (m, 2H, Ar−H), 8.15− 8.09 (m, 1H, Ar−H), 7.90 (m, 2H, Ar−H), 7.77−7.70 (m, 1H, Ar− H), 7.56 (s, 1H, Ar−H), 7.49 (d, J = 6.8 Hz, 3H, Ar−H), 7.18 (m, 3H, Ar−H), 7.06 (s, 1H, Ar−H), 2.30 (s, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 153.6, 153.5, 153.3, 140.9, 140.8, 139.2, 137.9, 137.3, 134.2, 130.9, 130.5, 129.9, 129.3, 129.2, 128.5, 128.2, 127.3, 127.1, 126.1, 124.9, 122.4, 120.8, 109.5, 21.5. IR (KBr, ν, cm−1) 3411, 3033, 1510, 1434, 1301, 1231, 1101, 1012, 973, 896, 778. HRMS (ESI-TOF) m/z [M − H]− calcd for C25H17N2O 361.1341; found 361.1323. 3-(3-(4-Ethylphenyl)quinoxalin-2-yl)naphthalen-1-ol (5f). Yellow solid; 63.2 mg, 84% yield; mp 226−228 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.28 (s, 1H, OH), 8.21−8.14 (m, 2H, Ar−H), 8.14−8.10 (m, 1H, Ar−H), 7.89 (m, 2H, Ar−H), 7.74 (m, 1H, Ar− H), 7.49 (m, 5H, Ar−H), 7.19 (d, J = 8.0 Hz, 2H, Ar−H), 7.05 (s, 1H, Ar−H), 2.60 (m, 2H, CH2), 1.16 (m, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 153.6, 153.4, 153.3, 145.1, 140.9, 140.8, 137.5, 136.6, 134.2, 130.8, 130.7, 130.1, 129.2, 128.5, 128.0,

2-(7-Fluoro-4-hydroxy-1-iodonaphthalen-2-yl)-1-phenylethanone (2z). White solid; 42.3 mg, 52% yield; mp 156−158 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.65 (s, 1H, OH), 8.25 (m, 1H, Ar−H), 8.12 (d, J = 7.6 Hz, 2H, Ar−H), 7.76 (m, 1H, Ar−H), 7.69 (m, 1H, Ar−H), 7.60 (m, 2H, Ar−H), 7.45−7.37 (m, 1H), 6.92 (s, 1H, Ar−H), 4.79 (s, 2H, CH2). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 196.8, 162.3 (1JCF = 242.9 Hz), 154.2, 141.5, 137.1 (5JCF = 7.9 Hz), 137.0, 133.9, 129.3, 128.6, 126.6 (4JCF = 9.6 Hz), 122.1, 115.6 (3JCF = 23.7 Hz), 115.5 (2JCF = 24.8 Hz), 111.9, 92.3, 52.5. IR (KBr, ν, cm−1) 3422, 3100, 1673, 1655, 1350, 1232, 1092, 1050, 941, 692. HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H13FIO2 406.9944; found 406.9961. General Procedure for the Synthesis of Products 3a−3c. Example for the Synthesis of 3a. A mixture of 1-(4-bromophenyl)-2(4-hydroxy-1-iodonaphthalen-2-yl)ethan-1-one (2d, 0.2 mmol), H2O (0.2 mmol), PdCl2(PPh3)2 (5 mol %), and Et3N (3.0 mL) was added to a 10 mL reaction vial, which was sealed and heated at 60 °C under O2 (1.0 atm) conditions for 5 h until TLC (petroleum ether/ethyl acetate 2:1) revealed that conversion of the starting material 2d was completed. When the reaction mixture was cooled to room temperature, the reaction mixture was poured into water (10 mL) and then extracted by ethyl acetate (10 mL). The organic phase was dried with anhydrous MgSO4 and collected and concentrated by vacuum distillation, which was purified by flash column chromatography (silica gel, mixtures of petroleum ether/acetic ester, 10:1, v/v) to afford the desired pure product 3a as a yellow solid. 1-(4-Bromophenyl)-2-(4-hydroxynaphthalen-2-yl)ethane-1,2dione (3a). Yellow solid; 54.5 mg, 77% yield; mp 180−182 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.86 (s, 1H, OH), 8.22 (d, J = 8.0 Hz, 1H, Ar−H), 8.08 (d, J = 8.0 Hz, 1H, Ar−H), 7.97 (s, 1H, Ar− H), 7.88 (m, 4H, Ar−H), 7.69 (m, 1H, Ar−H), 7.62 (m, 1H, Ar−H), 7.39 (s, 1H, Ar−H). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 195.1, 194.4, 154.9, 133.9, 133.1, 131.9, 130.6, 130.3, 129.4, 128.6, 128.2, 125.6, 122.7, 104.1. IR (KBr, ν, cm−1) 3467, 1672, 1654, 1596, 1414, 1281, 1091, 953, 840, 747, 680. HRMS (ESI-TOF) m/z [M − H]− calcd for C18H10BrO3, 352.9814; found 352.9808. 1-(4-Hydroxynaphthalen-2-yl)-2-(m-tolyl)ethane-1,2-dione (3b). Yellow solid; 38.0 mg, 65% yield; mp 166−168 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.85 (s, 1H, OH), 8.22 (d, J = 8.4 Hz, 1H, Ar−H), 8.08 (d, J = 8.0 Hz, 1H, Ar−H), 7.93 (s, 1H, Ar−H), 7.78− 7.72 (m, 2H, Ar−H), 7.69 (m, 1H, Ar−H), 7.61 (m, 2H, Ar−H), 7.52 (m, 1H, Ar−H), 7.39 (s, 1H, Ar−H), 2.40 (s, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 195.7, 195.6, 154.8, 139.6, 136.6, 133.9, 133.0, 130.8, 130.3, 130.1, 129.9, 129.3, 128.5, 128.2, 127.5, 125.2, 122.7, 104.2, 21.2. IR (KBr, ν, cm−1) 3466, 1677, 1658, 1567, 1402, 1281, 1064, 963, 827, 733, 671. HRMS (ESI-TOF) m/z [M − H]− calcd for C19H13O3 289.0865; found 289.0871. 1-(4-Ethylphenyl)-2-(4-hydroxynaphthalen-2-yl)ethane-1,2dione (3c). Yellow solid; 44.4 mg, 73% yield; mp 170−172 °C; 1H NMR (400 MHz, DMSO-d6; δ, ppm) 10.83 (s, 1H, OH), 8.21 (d, J = 8.4 Hz, 1H, Ar−H), 8.08 (d, J = 8.0 Hz, 1H, Ar−H), 7.93 (s, 1H, Ar− H), 7.87 (d, J = 8.0 Hz, 2H, Ar−H), 7.69 (m, 1H, Ar−H), 7.61 (m, 1H, Ar−H), 7.48 (d, J = 8.4 Hz, 2H, Ar−H), 7.38 (d, J = 1.2 Hz, 1H, Ar−H), 2.72 (m, 2H, CH2), 1.20 (m, 3H, CH3). 13C{1H} NMR (100 MHz, DMSO-d6; δ, ppm) 200.6, 199.9, 159.6, 157.6, 138.6, 135.6, 135.5, 135.1, 134.1, 134.0, 133.2, 132.9, 129.9, 127.4, 108.9, 33.6, 20.2. IR (KBr, ν, cm−1) 3466, 1677, 1658, 1567, 1402, 1281, 1064, 963, 827, 733, 671. HRMS (ESI-TOF) m/z [M − H]− calcd for C20H15O3 303.1021; found 303.1011. General Procedure for the Synthesis of Compounds 5a−5f. Example for the Synthesis of 5a. A mixture of 1-(4-fluorophenyl)-2(4-hydroxy-1-iodonaphthalen-2-yl)ethan-1-one (2a, 0.2 mmol), benzene-1,2-diamine (4, 0.3 mmol), PdCl2(PPh3)2 (5 mol %), and Et3N (3.0 mL) was added to a 10 mL reaction vial, which was sealed and heated at 60 °C under O2 (1.0 atm) conditions for 5 h until TLC (petroleum ether/ethyl acetate 4:1) revealed that conversion of the starting material 2a was completed. When the reaction mixture was cooled to room temperature, the reaction mixture was poured into water (10 mL) and then extracted by ethyl acetate (10 mL). The organic phase was dried with anhydrous MgSO4 and collected and 13341

DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343

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The Journal of Organic Chemistry 127.1, 126.1, 124.9, 122.4, 120.7, 109.5, 28.4, 15.8. IR (KBr, ν, cm−1) 3412, 3024, 1516, 1430, 1291, 1205, 1081, 1002, 963, 886, 763. HRMS (ESI-TOF) m/z [M − H]− calcd for C26H19N2O 375.1498; found 375.1503.

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417. (c) Lin, T. S.; Schinazi, R.; Griffith, B. P.; August, E. M.; Eriksson, B. H. F.; Zheng, D. K.; Prusoff, W. H. Selective inhibition of human immunodeficiency virus type 1 replication by the (−) but not the (+) enantiomer of gossypol. Antimicrob. Agents Chemother. 1989, 33, 2149−2151. (d) Meyers, A. I.; Willemsen, J. J. The synthesis of (S)-(+)-gossypol via an asymmetric Ullmann coupling. Chem. Commun. 1997, 1573−1574. (6) (a) Itokawa, H.; Mihara, K.; Takeya, K. Studies on a novel anthraquinone and its glycosides isolated from Rubia cordifolia and R. akane. Chem. Pharm. Bull. 1983, 31, 2353−2358. (b) Kawasaki, Y.; Goda, Y.; Yoshihira, K. The mutagenic constituents of Rubia tinctorum. Chem. Pharm. Bull. 1992, 40, 1504−1509. (c) Chung, M.-L.; Jou, S.-J.; Cheng, T.-H.; Lin, C.-N. Antiplatelet constituents of Formosan Rubia alkane. J. Nat. Prod. 1994, 57, 313−316. (d) Ho, L.K.; Don, M.-J.; Chen, H.-C.; Yeh, S.-F.; Chen, J.-M. Inhibition of hepatitis B surface antigen secretion on human hepatoma cells. Components from Rubia cordifolia. J. Nat. Prod. 1996, 59, 330−333. (7) (a) Koyama, K.; Natori, S.; Iitaka, Y. Absolute configurations of chaetochromin A and related bis(naphtho-γ-pyrone) mold metabolites. Chem. Pharm. Bull. 1987, 35, 4049−4055. (b) Itokawa, H.; Ibraheim, Z. Z.; Qiao, Y.-F.; Takeya, K. Anthraquinones, naphthohydroquinones and naphthohydroquinone dimers from Rubia cordifolia and their cytotoxic activity. Chem. Pharm. Bull. 1993, 41, 1869−1872. (c) Lumb, J.-P.; Choong, K. C.; Trauner, D. ortho-Quinone Methides from para-Quinones: Total Synthesis of Rubioncolin B. J. Am. Chem. Soc. 2008, 130, 9230−9231. (d) Morgan, B. J.; Mulrooney, C. A.; O’Brien, E. M.; Kozlowski, M. C. Perylenequinone natural products: total syntheses of the diastereomers (+)-phleichrome and (+)-calphostin D by assembly of centrochiral and axial chiral fragments. J. Org. Chem. 2010, 75, 30−43. (8) (a) Rinehart, K. L., Jr. Antibiotics with ansa rings. Acc. Chem. Res. 1972, 5, 57−64. (b) Meyers, A. I.; Willemsen, J. J. An oxazoline based approach to (S)-gossypol. Tetrahedron 1998, 54, 10493−10511. (c) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; WileyVCH: Weinheim, 2003. (d) Boonsri, S.; Karalai, C.; Ponglimanont, C.; Chantrapromma, S.; Kanjana-opas, A. Cytotoxic and Antibacterial Sesquiterpenes from Thespesia populnea. J. Nat. Prod. 2008, 71, 1173−1177. (9) (a) Liang, Q.; Xing, P.; Huang, Z.; Dong, J.; Sharpless, K. B.; Li, X.; Jiang, B. Palladium-Catalyzed, Ligand-Free Suzuki Reaction in Water Using Aryl Fluorosulfates. Org. Lett. 2015, 17, 1942−1945. (b) Adarsh, N.; Shanmugasundaram, M.; Avirah, R. R.; Ramaiah, D. Aza-BODIPY Derivatives: Enhanced Quantum Yields of Triplet Excited States and the Generation of Singlet Oxygen and their Role as Facile Sustainable Photooxygenation Catalysts. Chem. - Eur. J. 2012, 18, 12655−12662. (c) Lebrasseur, N.; Gagnepain, J.; OzanneBeaudenon, A.; Leger, J.-M.; Quideau, S. Efficient Access to Orthoquinols and Their [4 + 2] Cyclodimers via SIBX-Mediated Hydroxylative Phenol Dearomatization. J. Org. Chem. 2007, 72, 6280−6283. (10) (a) Wolthuis, E.; Bossenbroek, B.; DeWall, G.; Geels, E.; Leegwater, A. Reactions of methyl-substituted 1,4-epoxy-1,4-dihydronaphthalenes. J. Org. Chem. 1963, 28, 148−152. (b) Matsuzaka, H.; Hiroe, Y.; Iwasaki, M.; Ishii, Y.; Koyasu, Y.; Hidai, M. Construction of polycyclic systems by cyclocarbonylation. Part 3. A novel palladium- or platinum-catalyzed cyclocarbonylation reaction of cinnamyl compounds for synthesis of 1-naphthol derivatives. J. Org. Chem. 1988, 53, 3832−3838. (c) Batt, D. G.; Jones, D. G.; la Greca, S. Regioselectivity in the acid-catalyzed isomerization of 2-substituted 1,4-dihydro-1,4-epoxynaphthalenes. J. Org. Chem. 1991, 56, 6704− 6708. (d) Mulrooney, C. A.; Li, X.-L.; DiVirgilio, E. S.; Kozlowski, M. C. General Approach for the Synthesis of Chiral Perylenequinones via Catalytic Enantioselective Oxidative Biaryl Coupling. J. Am. Chem. Soc. 2003, 125, 6856−6857. (e) Peng, F.-Z.; Fan, B.-M.; Shao, Z.-H.; Pu, X.-W.; Li, P.-H.; Zhang, H.-B. Cu(OTf)2-catalyzed isomerization of 7-oxabicyclic alkenes: a practical route to the synthesis of 1naphthol derivatives. Synthesis 2008, 2008, 3043−3046. (f) Cui, L.Q.; Dong, Z.-L.; Zhang, C. Design, Synthesis, Structure, and Dehydrogenation Reactivity of a Water-Soluble o-Iodoxybenzoic

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b02108. 1 H and 13C NMR spectra for all pure products and X-ray structures of products 2a and 5e (PDF) Crystallographic data for 2a (CIF) Crystallographic data for 5e (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (Y.J.W.). *E-mail: [email protected] (S.J.T.). *E-mail: [email protected] (B.J.). ORCID

Bo Jiang: 0000-0003-3878-515X Author Contributions §

H.L. and P.Z. contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (Nos. 21472071 and 21602087), PAPD of Jiangsu Higher Education Institutions, the Outstanding Youth Fund of JSNU (YQ2015003), NSF of Jiangsu Province (BK20151137 and BK20160212), Xuzhou Social Development Fund (KC17130), and the Qing Lan Project of Jiangsu Education Committee.

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REFERENCES

(1) (a) Mason, R. T.; Talukder, M.; Kates, C. R. In Kirk-Othmer Encyclopedia of Chemical Technology, 4th ed.; Kirk, R. E., Ed.; Wiley: New York, 1995; Vol. 16. (b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis II; Wiley-VCH: Weinheim, 2003. (c) Nicolaou, K. C.; Montagnon, T. Molecules That Changed the World: A Brief History of the Art and Science of Synthesis and Its Impact on Society; Wiley-VCH: Weinheim, 2008. (2) Rappoport, Z. The Chemistry of Phenols; Wiley-VCH: Weinheim, 2003. (3) Hallock, Y. F.; Manfredi, K. P.; Blunt, J. W.; Cardellina, J. H., II; Schäffer, M.; Gulden, K.-P.; Bringmann, G.; Lee, A. Y.; Clardy, J. Korupensamines A-D, Novel Antimalarial Alkaloids from Ancistrocladus korupensis. J. Org. Chem. 1994, 59, 6349−6355. (4) (a) Itokawa, H.; Mihara, K.; Takeya, K. Studies on a novel anthraquinone and its glycosides isolated from Rubia cordifolia and R. akane. Chem. Pharm. Bull. 1983, 31, 2353−2358. (b) Kawasaki, Y.; Goda, Y.; Yoshihira, K. The mutagenic constituents of Rubia tinctorum. Chem. Pharm. Bull. 1992, 40, 1504−1509. (c) Chung, M.-L.; Jou, S.-J.; Cheng, T.-H.; Lin, C.-N.; Ko, F.-N.; Teng, C.-M. Antiplatelet constituents of Formosan Rubia alkane. J. Nat. Prod. 1994, 57, 313−316. (d) Ho, L.-K.; Don, M.-J.; Chen, H.-C.; Yeh, S.F.; Chen, J.-M. Inhibition of hepatitis B surface antigen secretion on human hepatoma cells. Components from Rubia cordifolia. J. Nat. Prod. 1996, 59, 330−333. (5) (a) Longmore, J. Cotton-Seed Oil: Its Colouring Matter and Mucilage, and Description of a New Method of Recovering the Loss Occurring in the Refining Process. Indian J. Chem. 1886, 5, 200. (b) National Coordinating Group on Male Fertility Agents. Gossypola new antifertility agent for males. China’s Med. 1978, 6, 13342

DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343

Article

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DOI: 10.1021/acs.joc.8b02108 J. Org. Chem. 2018, 83, 13335−13343