Rh(III)-Catalyzed Direct ortho-Chalcogenation of Phenols and Anilines

Nov 2, 2017 - A highly efficient Rh(III)-catalyzed direct C–H chalcogenation of phenols and anilines has been achieved with the assistance of the 2-...
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Rh(III)-Catalyzed Direct ortho-Chalcogenation of Phenols and Anilines Shiping Yang, Boya Feng, and Yudong Yang* Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, PR China S Supporting Information *

ABSTRACT: A highly efficient Rh(III)-catalyzed direct C−H chalcogenation of phenols and anilines has been achieved with the assistance of the 2-pyridyl group. The reaction features a broad substrate scope, good functional group tolerance, complete monothiolation selectivity, and easily removable directing group.

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INTRODUCTION 2-Hydroxylthiophenols are privileged structures in many natural products, pharmaceuticals, organic functional materials, and valuable synthetic intermediates.1 For instance, phenoxathiin and its derivatives are demonstrated as highly specific thrombin inhibitors;1a 2-phenylthiophenol and its derivatives can be served as glycine transporter-1 (GlyT-1) inhibitors;1b and phenoxathiin dioxide has been developed as electron-acceptor units for efficient blue thermally activated delayed fluorescence (TADF) emitters1d (Scheme 1). Current methods to access 2-hydroxylthiophenols include demethylation of the corresponding 2-methoxy aryl thioethers (Scheme 2a),2 transition-metalcatalyzed cross-coupling of 2-halo phenols with thiophenols (Scheme 2b),3 Lewis acid-mediated sulfenylation of phenols with disulfides4a or 1-(substituted phenylthio)pyrrolidine-2,5diones4b (Scheme 2c), iodine-promoted sulfenylation of cyclohexanones (Scheme 2d),5 and copper-catalyzed C−S coupling/ C−H hydroxylation of arylhalides6 or arylboronic acids7 with thiophenols/disulfides (Scheme 2e). Although these methods are reliable, they typically suffer from tedious synthetic routes, limited substrate scope, and/or low regioselectivity. Therefore, the development of a concise and efficient method to construct 2-hydroxylthiophenols is still in high demand. In the past decades, transition-metal-catalyzed C−H activation/functionalization has emerged as a powerful and effective strategy for the construction of synthetically useful synthons and complex molecules.8 However, the construction of the C(sp2)−S bond is always an important research area owing to the ubiquity of sulfur-containing molecules in pharmaceuticals and materials.9 In this context, transition-metal-catalyzed C−H thiolation reactions have also been developed with the assistance of a directing group.10 A diverse set of substrates such as benzoic acid,11 carbazole,12 indoline,13 indole,10c aniline,14 and naphthylamine15 derivatives have been successfully converted into the corresponding thiolated products based on this strategy. However, to the best of our knowledge, chelation-assisted C−H thiolation of phenols has not been reported. Herein we © 2017 American Chemical Society

disclose a Rh(III)-catalyzed directed C−H thiolation of phenols and anilines with disulfides as the sulfenylation reagent. This reaction features a complete monothiolation selectivity, good functional group tolerance, and easily removable directing group.

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RESULTS AND DISCUSSION Our investigation started by utilizing equimolar amounts of 2-phenoxypyridine 1a and p-tolyl disulfide 2a as the model substrates to optimize the reaction conditions (Table 1). To our delight, the desired product 3a could be obtained in 45% yield in the presence of [Cp*RhCl2]2 (5 mol %), AgOTf (20 mol %), and Cu(OAc)2·H2O (1.0 equiv) in toluene (Table 1, entry 1). Further screening of the oxidant indicated that Ag2O and Ag2CO3 were better oxidants for this reaction, giving the desired product 3a in 82% and 95% yields, respectively (Table 1, entries 2 and 3). However, no 3a product was observed when oxygen gas (1 atm) was used as the oxidant instead (Table 1, entry 4). Other solvents, such as DMF, PhCl, and 1,4-dioxane, were less effective (Table 1, entries 5−7). No reaction was observed in the absence of AgOTf (Table 1, entry 8). Typically, this reaction could be completed within 8 h (Table 1, entries 9−11). The reaction temperature proved to be critical to this reaction. Lowering the temperature would lead to a significantly diminished yield (Table 1, entries 12 and 13). With the optimal conditions in hands, we next explored the substrate scope with respect to phenols (Scheme 3). Gratifyingly, a diverse set of substituted phenols could react with p-tolyl disulfide under the standard conditions to afford the corresponding 2-sulfanylphenols in moderate to excellent yields. The position of the substituents on the phenol rings showed a significant effect on the yields (3b vs 3c, 3d vs 3g). Phenols 1 bearing both electron-donating and electron-withdrawing substituents were competent substrates in this transformation although higher yields were typically observed in the former case Received: September 4, 2017 Published: November 2, 2017 12430

DOI: 10.1021/acs.joc.7b02221 J. Org. Chem. 2017, 82, 12430−12438

Article

The Journal of Organic Chemistry Scheme 1. Selected Examples of 2-Hydroxylthiophenol Derivatives

Scheme 2. Strategies for the Synthesis of 2-Hydroxylthiophenols

Table 1. Optimization of the Reaction Conditionsa

entry

oxidant

solvent

time (h)

yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

Cu(OAc)2·H2O Ag2O Ag2CO3 O2 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3

toluene toluene toluene toluene DMF PhCl dioxane toluene toluene toluene toluene toluene toluene

24 24 24 24 24 24 24 24 16 8 6 8 8

45 82 95 nd trace 86 85 ndc 95 96 72 61d 37e

standard conditions (3d−3j). In addition, 2-(naphthalen-1yloxy)pyridine 1k also proved to be a suitable substrate, delivering the desired product 3k in an almost quantitative yield. It is worth noting that only monothiolated products were observed in this transformation. To further test the substrate scope of the reaction, we investigated the generality of disulfides (Scheme 4). Diaryl disulfides with both the electron-donating groups such as methoxy and electron-withdrawing groups such as chloro and bromo worked well under the standard conditions (4b−4g). However, the disulfides having electron-donating substituents typically resulted in higher yields than the substrates having electronwithdrawing substituents. Furthermore, benzyl disulfide, exemplified by 2i, smoothly reacted with 1a to deliver the corresponding product in 61% yield (4i). Because 2-aminothiophenols and their Selena analogues are key structural motifs in materials, pharmaceuticals, and bioactive natural products,16 we then tried to extend our method to anilines and disulfides. Gratifyingly, we found that anilines could be easily thiolated at the ortho-position under [Cp*RhCl2]2 (5 mol %), AgOTf (20 mol %), and Ag2O (0.2 mmol) in toluene (1.0 mL) at 100 °C for 24 h (Scheme 5). Likewise, this rhodium catalytic system exhibited a wide substrate scope for both anilines and disulfides, giving a variety of 2-aminothiophenols in moderate to good yields. Notably, dialkyl disulfide such as dimethyl disulfide was also compatible with the catalytic system, leading to the methylthiolated product in a moderate yield (6l). In addition,

a

Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), [Cp*RhCl2]2 (5 mol %), AgOTf (20 mol %), oxidant (1.0 equiv), solvent (1.0 mL), heating in a sealed tube, under air. bIsolated yield after column chromatography. cNo AgOTf. d100 °C. e80 °C.

(3f−3j). A variety of functional groups such as methyl, methoxy, chloro, acetamido, acetyl, and ester could be tolerated under the 12431

DOI: 10.1021/acs.joc.7b02221 J. Org. Chem. 2017, 82, 12430−12438

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The Journal of Organic Chemistry Scheme 3. Scope of 2-Aryloxypyridinesa,b

Reaction conditions: 1 (0.2 mmol), 2a (0.2 mmol), [Cp*RhCl2]2 (5 mol %), AgOTf (20 mol %), Ag2CO3 (0.2 mmol), toluene (1.0 mL), 130 °C, 8 h, under air. bIsolated yield after column chromatography. c1.2 mmol scale. d1d (0.3 mmol) was used. e1 (0.4 mmol) was used.

a

[D5]-1a, implying that the C−H cleavage might not be involved in the rate-determining step (Scheme 8c). On the basis of the above results and the previous literature reports,10a,d,11b,c a proposed catalytic cycle of the Rh(III)catalyzed ortho-chalcogenation of phenols was depicted. Initially, the reaction of [Cp*RhCl2]2 with AgOTf gives a cationic Rh(III) species, which could facilitate a reversible C−H activation process to produce a six-membered rhodacycle species A. Then, intermediate A undergoes a nucleophilic addition with diphenyl disulfide (2a) to deliver the target product 3a and release the species B (path a). Alternatively, oxidative addition of intermediate A to diphenyl disulfide provides a Rh(V) species10a,18 C, which further undergoes a reductive elimination to afford the product 3a and Rh(III) species B (path b). Then, the Rh(III) species B could participate in a second C−H activation to afford the rhodacycle intermediate D. Finally, reductive elimination of the rhodacycle D generates 3a and a Rh(I) species, which is oxidized by Ag2CO3 to regenerate the reactive Rh(III) species to complete the catalytic cycle (Scheme 9).

an attempt of anilines with diphenyl diselenide was tested, affording the corresponding selenated product in 70% yield (6m). Likewise, only the monothiolated products were observed under the standard conditions, which are different from the previous report.14 The directing group could be easily removed through the reported method, affording the corresponding 2-(arylthio)phenol 7 and 2-aminothiophenol 8 in moderate yields (Scheme 6). To further demonstrate the utility of this protocol, we investigated the synthetic potential of this reaction. As shown in Scheme 6, the removal of the pyridyl group and following the intramolecular C−O cross-coupling produced the phenoxathiine 10 (Scheme 7a). As benzimidazole-fused heterocycles are often encountered in pharmaceuticals and material molecules,17 compound 6a was treated with I2 and K2CO3 at 60 °C, providing pyrido[1,2-a]benzimidazole derivatives 11 in 60% yield (Scheme 7b). To probe the reaction mechanism, several control experiments were performed. The intermolecular competition experiment between phenols with different electronic nature selectively yielded the methyl-substituted phenol 3c as the major product, suggesting that an aromatic electrophilic substitution process might be involved (Scheme 8a). Treatment of 2-phenoxypyridine 1a with D2O led to a significant deuterium scrambling, indicating that the C−H activation is reversible (Scheme 8b). In addition, a kinetic isotopic effect (KIE) of 1.35 was obtained in the intermolecular competitive experiment between 1a and

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CONCLUSION In summary, we have developed a Rh(III)-catalyzed direct orthochalcogenation of phenols and anilines with disulfides as the thiolation reagents. This reaction features a broad substrate scope, good functional group tolerance, complete monothiolation 12432

DOI: 10.1021/acs.joc.7b02221 J. Org. Chem. 2017, 82, 12430−12438

Article

The Journal of Organic Chemistry Scheme 4. Scope of Disulfidesa,b

Scheme 6. Removal of the Directing Group

we believe this protocol should be potentially useful in the medical, material, and natural product chemistry studies. Further applications of this reaction are ongoing in our laboratory.

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EXPERIMENTAL SECTION

General Information. NMR spectra were obtained on an Agilent 400-MR DD2 spectrometer. The 1H NMR (400 MHz) chemical shifts were measured relative to CDCl3 as the internal reference (CDCl3 δ 7.26 ppm). The 13C NMR (100 MHz) chemical shifts were given using CDCl3 as the internal standard (CDCl3 δ 77.16 ppm). Melting points were determined with an SGW X-4 and were uncorrected. Infrared (IR) spectra were recorded on a Shimadzu IRTracer-100 FT-IR spectrophotometer. Frequencies were given in reciprocal centimeters (cm−1) and only selected absorbencies are reported. High-resolution mass spectra (HRMS) were obtained with a Shimadzu LCMS-IT-TOF (ESI). Unless otherwise noted, all reagents were obtained from commercial suppliers and used without further purification. [Cp*RhCl2]2,19a 2-aryloxypyridines,19b pyridinyl arylamines,19c and [D5]-1a19d were prepared according to the literature procedures. All solvents were used without further purification. General Process for the Rh(III)-Catalyzed Direct orthoThiolation of Phenols. Under air, a dry Schlenk tube with a magnetic stir bar was charged with 2-aryloxypyridines (0.2 mmol), disulfides (0.2 mmol), [Cp*RhCl2]2 (6.2 mg, 5 mol %), AgOTf (10.3 mg, 20 mmol %), Ag2CO3 (55 mg, 1.0 equiv), and toluene (1 mL). The mixture was stirred at 130 °C for 8 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature and the solvent was evaporated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel to provide the desired product. General Process for the Rh(III)-Catalyzed Direct orthoThiolation of Anilines. Under air, a dry Schlenk tube with a magnetic stir bar was charged with pyridinyl arylamines (0.2 mmol), disulfides (0.3 mmol), [Cp*RhCl2]2 (6.2 mg, 5 mol %), AgOTf (10.3 mg, 20 mmol %), Ag2O (46 mg, 1.0 equiv), and toluene (1 mL). The mixture was stirred at 100 °C for 24 h. After completion of the reaction, the reaction mixture was cooled to ambient temperature. The solvent was evaporated under reduced pressure, and the resulting residue was purified by flash column chromatography on silica gel to provide the desired product. Synthesis of Compound 7. To a well-stirred solution of 3a (0.5 mmol) in dry toluene (5 mL), under an N2 atmosphere, was added MeOTf (166.0 μL, 1.5 mmol) at 100 °C. Then, the mixture was stirred for 2 h. After cooling to ambient temperature, the mixture was concentrated in vacuo. Without purification, the crude product was subsequently added into a solution of NaOMe (675.1 mg, 12.5 mmol) in 4 mL of MeOH under an N2 atmosphere, heated to reflux, and stirred for a further 30 min. After cooling the mixture to ambient temperature, the solvent was evaporated by rotary evaporation. Water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phase was washed with brine, dried over Mg2SO4, filtered, and concentrated under a vacuum. The crude product was further purified by flash column chromatography using petroleum/ ethyl acetate (40/1, v/v) as the eluent to afford the desired product 7 as a dark and white solid (54 mg, 50% yield).

a

Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), [Cp*RhCl2]2 (5 mol %), AgOTf (20 mol %), Ag2CO3 (0.2 mmol), toluene (1.0 mL), 130 °C, 8h, under air. bIsolated yield after column chromatography. c1a (0.4 mmol).

Scheme 5. Scope of Aniline and Disulfide Substratesa,b

a

Reaction conditions: 5 (0.2 mmol), 2 (0.3 mmol), [Cp*RhCl2]2 (5 mol %), AgOTf (20 mol %), Ag2O (0.2 mmol), toluene (1.0 mL), 100 °C, 24 h, under air. bIsolated yield after column chromatography. c 1.2 mmol scale. dDiphenyl diselenide (0.3 mmol) was used.

selectivity, and removable directing groups. Owing to the high synthetic value of 2-hydroxythiophenols and 2-aminothiophenols, 12433

DOI: 10.1021/acs.joc.7b02221 J. Org. Chem. 2017, 82, 12430−12438

Article

The Journal of Organic Chemistry Scheme 7. Synthesis of Phenoxathiin and Pyrido[1,2-a]benzimidazole Derivatives

Synthesis of Compound 10. To a well-stirred solution of 4f (0.5 mmol) in dry toluene (5 mL), under an N2 atmosphere, was added MeOTf (166.0 μL, 1.5 mmol) at 100 °C. Then, the mixture was stirred for 2 h. After cooling to ambient temperature, the mixture was concentrated in vacuo. Without purification, the crude product was subsequently added into NaOMe (675.1 mg, 12.5 mmol) in 4 mL of MeOH under an N2 atmosphere, heated to reflux, and stirred for a further 30 min. After cooling the mixture to ambient temperature, the solvent was evaporated by rotary evaporation. Water (15 mL) was added to the residue, and the mixture was extracted with ethyl acetate (3 × 15 mL). The combined organic phase was washed with brine, dried over Mg2SO4, filtered, and concentrated under a vacuum. The crude product was further purified by flash column chromatography using petroleum/DCM (30/1, v/v) as the eluent to afford the desired product 9 as a colorless oil (80 mg, 57% yield). Subsequently, CuTc (copper(I) thiophene-2-carboxylate) (0.286 mmol) was added to a solution of sulfide 9 (0.286 mmol) in DMAC (9.5 mL). The mixture was heated to 100 °C and stirred for 3 h. Then, water (20 mL) was added, and the mixture was extracted with ethyl acetate (2 × 10 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was further purified by silica gel chromatography using pure hexane as an eluent to afford the desired product 10 as a white solid (35.4 mg, 62% yield). Synthesis of Compound 11. I2 (76 mg, 3.0 equiv) and K2CO3 (55.3 mg, 4.0 equiv) were added to a stirred solution of 6a (30.6 mg, 0.1 mmol) in 1,4-dioxane (2 mL) sequentially. The mixture was heated to 60 °C and stirred until TLC implied that the conversion was complete. After the mixture cooled to room temperature, 5% Na2S2O3 (10 mL) was added, and the mixture was extracted with EtOAc (3 × 10 mL). Then, the organic layer was dried over Na2SO4, filtered, and evaporated under a vacuum. The residue was purified by silica gel chromatography using petroleum/ethyl acetate (3/1, v/v) as the eluent to afford the desired product 11 as a yellow solid (18.2 mg, 60% yield). 2-(2-(p-Tolylthio)phenoxy)pyridine (3a). Purification by column chromatography on silica gel (petroleum ether/ethyl acetate = 25/1, v/v) afforded 3a as a white solid (56 mg, 95% yield). Mp: 112−114 °C. 1 H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 6.91 (d, J = 8.0 Hz, 1H), 6.96−6.99 (m, 1H), 7.10−7.15 (m, 5H), 7.22−7.25 (m, 1H), 7.29−7.31 (m, 2H), 7.65−7.68 (m, 1H), 8.15−8.17 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.3, 111.4, 118.5, 122.8, 125.8, 127.7, 130.0, 130.2, 131.1, 133.2, 133.7, 138.0, 139.5, 147.7, 151.5, 163.5 ppm. IR (KBr): 2870, 1668, 1099, 816, 748, 723 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16NOS, 294.0953; found, 294.0948. 2-(2-Methyl-6-(p-tolylthio)phenoxy)pyridine (3b). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 25/1, v/v) afforded 3b as a white solid (56 mg, 92% yield). Mp: 89−91 °C. 1 H NMR (400 MHz, CDCl3): δ 2.15 (s, 3H), 2.32 (s, 3H), 6.90−6.94 (m, 3H), 7.02 (t, J = 8.0 Hz, 1H), 7.06−7.13 (m, 3H), 7.26−7.28 (m, 2H), 7.67 (t, J = 7.2 Hz, 1H), 8.13 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 16.9, 21.3, 110.4, 118.1, 126.0, 128.5, 129.3, 130.1, 130.2, 131.8, 132.4, 133.3, 137.9, 139.4, 147.8, 149.5, 163.0 ppm. IR (KBr): 2966, 2897, 1606, 1130, 1089, 875, 854, 763 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18NOS, 308.1109; found, 308.1102.

Scheme 8. Mechanistic Studies

Scheme 9. Proposed Mechanism

Synthesis of Compound 8. A well-stirred solution of 6a (61.3 mg, 0.2 mmol) and MeOTf (56 mg, 0.34 mmol) in dichloromethane (8 mL) was stirred at 80 °C for 6 h. After the solution was cooled to ambient temperature, the solution was concentrated under a vacuum. A small amount of methanol (1 mL) was added to the residue; then the mixed solution of hydrazine/acetic acid (5 mL/1.4 mL) was added. The mixture was heated to 130 °C and stirred for 24 h. After the mixture was cooled to ambient temperature, water (10 mL) was added and the mixture was extracted with DCM (3 × 5 mL). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was further purified by silica gel chromatography using petroleum/ethyl acetate (40/1, v/v) as the eluent to afford the desired product 8 as a colorless oil (27.5 mg, 60% yield). 12434

DOI: 10.1021/acs.joc.7b02221 J. Org. Chem. 2017, 82, 12430−12438

Article

The Journal of Organic Chemistry 2-(5-Methyl-2-(p-tolylthio)phenoxy)pyridine (3c). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 25/1, v/v) afforded 3c as a colorless oil (47 mg, 77% yield). 1H NMR (400 MHz, CDCl3): δ 2.30 (s, 3H), 2.34 (s, 3H), 6.88 (d, J = 8.4 Hz, 1H), 6.94−6.98 (m, 3H), 7.06 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 8.14 (s, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 21.2, 21.3, 111.4, 118.3, 123.6, 126.5, 126.9, 130.0, 131.4, 132.0, 132.5, 137.2, 138.9, 139.4, 147.6, 152.2, 163.6 ppm. IR (KBr): 2962, 2889, 1699, 1091, 1074, 900, 794, 741, 677 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18NOS, 308.1109; found, 308.1102. 2-(5-Methoxy-2-(p-tolylthio)phenoxy)pyridine (3d). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 3d as a white solid (46 mg, 71% yield). Mp: 80−82 °C. 1 H NMR (400 MHz, CDCl3): δ 2.28 (s, 3H), 3.79 (s, 3H), 6.75 (d, J = 7.6 Hz, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 6.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 8.8 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 8.12 (d, J = 4.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.1, 55.7, 108.9, 111.4, 112.2, 118.4, 119.5, 129.7, 130.1, 133.1, 135.7, 136.3, 139.4, 147.6, 154.7, 160.8, 163.5 ppm. IR (KBr): 2920, 2860, 1620, 1155, 1083, 1072, 864, 781, 688 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18NO2S, 324.1058; found, 324.1050. 2-(4,5-Dimethyl-2-(p-tolylthio)phenoxy)pyridine (3e). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 3e as a colorless oil (48 mg, 75% yield). 1H NMR (400 MHz, CDCl3): δ 2.18 (s, 3H), 2.24 (s, 3H), 2.30 (s 3H), 6.86 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 6.0 Hz, 1H), 6.97 (s, 1H), 7.04 (d, J = 7.6 Hz, 2H), 7.09 (s, 1H), 7.20 (d, J = 7.6 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 8.13 (d, J = 4.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 19.3, 19.8, 21.2, 111.2, 118.1, 124.2, 125.9, 129.8, 131.3, 132.0, 134.2, 134.5, 136.8, 137.7, 139.3, 147.6, 150.6, 163.8 ppm. IR (KBr): 2953, 2858, 1668, 1232, 1178, 852, 702 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H20NOS, 322.1266; found, 322.1257. 2-(5-Chloro-2-(p-tolylthio)phenoxy)pyridine (3f). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 25/1, v/v) afforded 3f as a colorless oil (37 mg, 56% yield). 1H NMR (400 MHz, CDCl3): δ 2.32 (s, 3H), 6.93 (d, J = 8.4 Hz, 1H), 7.00−7.06 (m, 3H), 7.10 (d, J = 7.6 Hz, 2H), 7.14 (s, 1H), 7.27 (d, J = 7.6 Hz, 2H), 7.69 (t, J = 7.6 Hz, 1H), 8.15 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.3, 111.6, 118.9, 123.1, 126.0, 129.4, 129.9, 130.3, 131.7, 132.7, 133.3, 138.3, 139.7, 147.6, 151.8, 162.9 ppm. IR (KBr): 2891, 1427, 1091, 869, 775, 696 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H15ClNOS, 328.0563; found, 328.0561. 2-(4-Methoxy-2-(p-tolylthio)phenoxy)pyridine (3g). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 10/1, v/v) afforded 3g as a white solid (56 mg, 86% yield). Mp: 77−79 °C. 1H NMR (400 MHz, CDCl3): δ 2.33 (s, 3H), 3.69 (s, 3H), 6.61 (s, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 6.93−6.97 (m, 1H), 7.06−7.12 (m, 3H), 7.30 (d, J = 7.6 Hz, 2H), 7.65 (t, J = 6.4 Hz, 1H), 8.16 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.3, 55.6, 111.1, 112.6, 115.8, 118.2, 123.6, 129.3, 130.2, 132.4, 133.5, 138.2, 139.4, 144.7, 147.6, 157.1, 163.8 ppm. IR (KBr): 2970, 2835, 1651, 1197, 860 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18NO2S, 324.1058; found, 324.1050. N-(4-(Pyridin-2-yloxy)-3-(p-tolylthio)phenyl)acetamide (3h). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 3/1, v/v) afforded 3h as a pale-yellow solid (65 mg, 93% yield). Mp: 99−101 °C. 1H NMR (400 MHz, CDCl3): δ 2.01 (s, 3H), 2.30 (s, 3H), 6.92 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 7.06−7.09 (m, 3H), 7.27 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.82 (s, 1H), 8.10 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.3, 24.5, 111.5, 118.6, 119.4, 121.6, 123.0, 129.0, 130.2, 131.7, 133.5, 135.9, 138.3, 139.7, 147.1, 147.2, 163.6, 168.5 ppm. IR (KBr): 3367, 2862, 1639, 1141, 839 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19N2O2S, 351.1167; found, 351.1159. 1-(4-(Pyridin-2-yloxy)-3-(p-tolylthio)phenyl)ethanone (3i). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 10/1, v/v) afforded 3i as a white solid (43 mg, 65% yield). Mp: 72−74 °C. 1H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 2.46 (s, 3H), 6.97 (d, J = 8.0 Hz, 1H), 7.02 (t, J = 6.0 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H),

7.20 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H), 7.72 (t, J = 7.6 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 4.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.3, 26.6, 112.0, 119.2, 122.3, 127.8, 129.0, 130.4, 131.2, 131.9, 133.4, 134.5, 138.6, 139.8, 147.7, 155.4, 162.8, 196.7 ppm. IR (KBr): 2922, 1687, 1085, 950, 842 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H18NO2S, 336.1058; found, 336.1054. Methyl 3-(Pyridin-2-yloxy)-4-(p-tolylthio)benzoate (3j). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 10/1, v/v) afforded 3j as a colorless oil (38 mg, 55% yield). 1 H NMR (400 MHz, CDCl3): δ 2.38 (s, 3H), 3.86 (s, 3H), 6.91 (d, J = 8.4 Hz, 1H), 7.01 (t, J = 7.6 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.70 (t, J = 8.4 Hz, 2H), 7.76 (s, 1H), 8.17 (d, J = 4.4 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.4, 52.3, 111.6, 118.9, 123.3, 126.6, 127.3, 128.0, 128.3, 130.6, 135.0, 139.2, 139.5, 139.7, 147.7, 149.8, 163.0, 166.4 ppm. IR (KBr): 2893, 1732, 1105, 871, 761, 711 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H18NO3S, 352.1007; found, 352.0999. 2-(2-(p-Tolylthio)naphthalen-1-yloxy)pyridine (3k). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 3k as a white solid (70 mg, 99% yield). Mp: 136−138 °C. 1H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 6.97 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 6.8 Hz, 2H), 7.25 (d, J = 9.6 Hz, 1H), 7.31 (d, J = 7.2 Hz, 2H), 7.40−7.48 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.85 (dd, J = 19.6 Hz, 4.8 Hz, 2H), 8.11 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.3, 110.5, 118.4, 122.1, 126.1, 126.3, 126.9, 127.2, 128.0, 128.2, 128.4, 130.1, 130.6, 132.8, 133.6, 137.8, 139.6, 147.0, 147.9, 163.8 ppm. IR (KBr): 2906, 1685, 1143, 756 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H18NOS, 344.1109; found, 344.1110. 2-(6-(p-Tolylthio)benzo[d][1,3]dioxol-5-yloxy)pyridine (3l). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 3l as a white solid (28 mg, 42% yield). Mp: 83−85 °C. 1H NMR (400 MHz, CDCl3): δ 2.26 (s, 3H), 6.00 (s, 2H), 6.71 (d, J = 7.6 Hz, 1H), 6.84 (t, J = 8.0 Hz, 2H), 6.88−6.92 (m, 1H), 6.98 (d, J = 7.2 Hz, 2H), 7.11 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 1H), 8.07 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.1, 102.2, 108.9, 109.9, 111.1, 115.5, 118.1, 129.1, 129.6, 131.8, 136.2, 139.3, 145.0, 147.4, 149.0, 150.4, 164.1 ppm. IR (KBr): 2956, 2920, 1602, 1120, 854, 812, 731 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H16NO3S, 338.0851; found, 338.0845. 2-(2-(Phenylthio)phenoxy)pyridine (4a). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4a as a white solid (55 mg, 99% yield). Mp: 63−65 °C. 1H NMR (400 MHz, CDCl3): δ 6.87−6.94 (m, 2H), 7.00 (s, 1H), 7.09− 7.18 (m, 1H), 7.25−7.30 (m, 4H), 7.31−7.39 (m, 3H), 7.651−7.70 (m, 1H), 8.10−8.12 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 111.4, 118.5, 123.0, 125.9, 127.4, 128.4, 129.2, 129.8, 132.0, 132.5, 134.5, 139.5, 147.6, 152.4, 163.5 ppm. IR (KBr): 1654, 1099, 1024, 746 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H14NOS, 280.0796; found, 280.0787. 2-(2-(4-Methoxyphenylthio)phenoxy)pyridine (4b). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 15/1, v/v) afforded 4b as a white solid (56.4 mg, 92% yield). Mp: 83−85 °C. 1H NMR (400 MHz, CDCl3): δ 3.81 (s, 3H), 6.86 (d, J = 8.4 Hz, 2H), 6.94−6.99 (m, 3H), 7.05−7.12 (m, 2H), 7.18−7.24 (m, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 8.18 (s, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 55.5, 111.3, 115.1, 118.5, 122.6, 123.0, 125.8, 127.0, 129.6, 132.4, 136.1, 139.5, 147.7, 150.6, 160.0, 163.4 ppm. IR (KBr): 2924, 1695, 1064, 756 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16NO2S, 310.0902; found, 310.0898. 2-(2-(2-Methoxyphenylthio)phenoxy)pyridine (4c). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 15/1, v/v) afforded 4c as a pale-yellow solid (50 mg, 81% yield). Mp: 64−66 °C. 1H NMR (400 MHz, CDCl3): δ 3.81 (s, 3H), 6.86−6.92 (m, 3H), 6.93−6.98 (m, 1H), 7.13 (t, J = 7.2 Hz, 1H), 7.16−7.23 (m, 4H), 7.30 (t, J = 7.2 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 8.14 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 55.9, 110.9, 111.5, 118.5, 121.3, 122.4, 122.8, 125.7, 128.3, 128.5, 128.8, 132.5, 133.0, 139.4, 147.6, 152.7, 158.0, 163.5 ppm. IR (KBr): 2937, 1676, 1139, 746, 750 cm−1. 12435

DOI: 10.1021/acs.joc.7b02221 J. Org. Chem. 2017, 82, 12430−12438

Article

The Journal of Organic Chemistry HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16NO2S, 310.0902; found, 310.0911. 2-(2-(4-Chlorophenylthio)phenoxy)pyridine (4d). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4d as a white solid (41 mg, 66% yield). Mp: 100− 102 °C. 1H NMR (400 MHz, CDCl3): δ 6.87 (d, J = 8.4 Hz, 1H), 6.94− 6.98 (m, 1H), 7.15−7.20 (m, 3H), 7.21−7.24 (m, 3H), 7.29−7.36 (m, 2H), 7.66 (t, J = 8.0 Hz, 1H), 8.12 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 111.4, 118.6, 123.2, 126.0, 128.9, 129.1, 129.3, 132.7, 133.1, 133.2, 133.6, 139.5, 147.6, 152.7, 163.4 ppm. IR (KBr): 1662, 1097, 819, 752 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13ClNOS, 314.0406; found, 314.0405. 2-(2-(4-Bromophenylthio)phenoxy)pyridine (4e). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4e as a white solid (46 mg, 64% yield). Mp: 114− 116 °C. 1H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 8.4 Hz, 1H), 6.93− 6.98 (m, 1H), 7.15−7.20 (m, 4H), 7.31−7.36 (m, 4H), 7.66 (t, J = 8.0 Hz, 1H), 8.11 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 111.4, 118.6, 121.2, 123.3, 126.0, 128.6, 129.2, 132.2, 132.8, 133.4, 134.4, 139.5, 147.5, 152.29, 163.3 ppm. IR (KBr): 1649, 1087, 812, 752, 555 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13BrNOS, 357.9901; found, 357.9893. 2-(2-(4-Bromophenylthio)phenoxy)pyridine (4f). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4f as a yellow oil (43 mg, 60% yield). 1H NMR (400 MHz, CDCl3): δ 6.85 (d, J = 8.4 Hz, 1H), 6.91−6.96 (m, 1H), 7.00 (t, J = 7.2 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.20−7.24 (m, 2H), 7.41 (d, J = 7.2 Hz, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 8.08 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 111.6, 118.6, 123.4, 123.8, 126.1, 126.7, 127.6, 127.8, 130.1, 131.0, 133.0, 135.0, 137.4, 139.5, 147.5, 154.1, 163.3 ppm. IR (KBr): 1652, 1066, 812, 752, 744, 569 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13BrNOS, 357.9901; found, 357.9899. 2-(2-(2,4-Dichlorophenylthio)phenoxy)pyridine (4g). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 25/1, v/v) afforded 4g as a flaxen oil (41 mg, 59% yield). 1H NMR (400 MHz, CDCl3): δ 6.86 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 6.0 Hz, 1H), 6.99−7.06 (m, 2H), 7.21−7.26 (m, 2H), 7.31−7.33 (m, 1H), 7.42−7.46 (m, 2H), 7.62−7.67 (m, 1H), 8.07 (d, J = 4.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 111.6, 118.8, 123.6, 125.9, 126.2, 127.5, 129.5, 130.4, 131.7, 132.6, 134.21, 134.23, 135.2, 139.6, 147.5, 154.2, 163.3 ppm. IR (KBr): 1647, 1097, 869, 771, 721 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H12Cl2NOS, 348.0017; found, 348.0011. 2-(2-(Naphthalen-2-ylthio)phenoxy)pyridine (4h). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4h as a white solid (55 mg, 84% yield). Mp: 99−101 °C. 1 H NMR (400 MHz, CDCl3): δ 6.95 (d, J = 9.6 Hz, 2H), 7.06 (d, J = 7.2 Hz, 1H), 7.43−7.48 (m, 4H), 7.65 (s, 1H), 7.75−7.80 (m, 5H), 7.90 (m, 1H), 8.12 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 110.9, 118.5, 126.5, 126.6, 126.7, 127.7, 127.8, 129.0, 129.96, 130.03, 131.1, 132.0, 132.50, 132.54, 132.7, 133.8, 139.5, 147.4, 147.6, 149.4, 162.8 ppm. IR (KBr): 1668, 1107, 817, 744 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H16NOS, 330.0953; found, 330.0949. 2-(2-(Benzylthio)phenoxy)pyridine (4i). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 4i as a white solid (36 mg, 61% yield). Mp: 124−126 °C. 1H NMR (400 MHz, CDCl3): δ 4.08 (s, 2H), 6.92 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 7.12−7.15 (m, 2H), 7.23−7.26 (m, 6H), 7.35 (d, J = 7.2 Hz, 1H), 7.69 (t, J = 7.2 Hz, 1H), 8.18 (m, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 37.9, 111.2, 118.5, 122.6, 125.7, 127.3, 127.9, 128.5, 129.1, 129.6, 131.4, 137.2, 139.5, 147.8, 152.5, 163.5 ppm. IR (KBr): 1654, 1101, 758, 711, 719 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16NOS, 294.0953; found, 294.0953. N-(4-Methyl-2-(p-tolylthio)phenyl)pyridin-2-amine (6a). Purification by column chromatography on silica gel (petroleum ether/ethyl acetate = 20/1, v/v) afforded 6a as a pale-red oil (42 mg, 68% yield). 1 H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H), 2.29 (s, 3H), 6.67−6.73 (m, 2H), 7.01−7.09 (m, 4H), 7.17−7.22 (m, 2H), 7.32 (s, 1H), 7.44 (t, J = 6.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 20.7, 21.1, 110.0, 115.4, 119.7, 121.9, 128.4,

130.1, 130.8, 132.1, 132.5, 136.2, 136.3, 137.5, 139.6, 148.2, 155.6 ppm. IR (KBr): 3327, 2891, 1647, 1139, 829, 754 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2S, 307.1269; found, 307.1260. N-(2-(p-Tolylthio)phenyl)pyridin-2-amine (6b). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 6b as a pale-yellow solid (34 mg, 58% yield). Mp: 65−67 °C. 1H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H), 6.74 (t, J = 7.2 Hz, 2H), 6.97 (t, J = 7.6 Hz, 1H), 7.02−7.09 (m, 4H), 7.36−7.42 (m, 2H), 7.45−7.52 (m, 2H), 8.20−8.25 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.1, 110.6, 115.8, 118.8, 121.1, 122.1, 128.3, 130.1, 130.3, 132.4, 136.2, 136.3, 137.6, 142.2, 148.1, 155.2 ppm. IR (KBr): 3369, 2899, 1676, 1143, 804, 754 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17N2S, 293.1112; found, 293.1104. N-(5-Methoxy-2-(p-tolylthio)phenyl)pyridin-2-amine (6c). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 15/1, v/v) afforded 6c as a yellow solid (50 mg, 77% yield). Mp: 73−75 °C. 1H NMR (400 MHz, CDCl3): δ 2.25 (s, 3H), 3.87 (s, 3H), 6.54 (d, J = 8.0 Hz, 1H), 6.71−6.77 (m, 2H), 7.00 (m, 4H), 7.46−7.52 (m, 2H), 7.62 (s, 1H), 8.13 (s, 1H), 8.25 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.0, 55.5, 103.7, 107.4, 109.9, 111.3, 115.9, 126.6, 130.0, 133.8, 135.5, 137.6, 138.4, 144.3, 148.0, 155.0, 162.0 ppm. IR (KBr): 3342, 2906, 1685, 1139, 864, 808, 759 cm−1. HRMS (ESITOF) m/z: [M + H]+ calcd for C19H19N2OS, 323.1218; found, 323.1213. N-(4-Chloro-2-(p-tolylthio)phenyl)pyridin-2-amine (6d). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 6d as a yellow solid (40 mg, 61% yield). Mp: 101−103 °C. 1H NMR (400 MHz, CDCl3): δ 2.29 (s, 3H), 6.66 (d, J = 8.4 Hz, 1H), 6.75−6.81 (m, 1H), 7.06−7.13 (m, 4H), 7.30 (d, J = 8.8 Hz, 2H), 7.44 (s, 1H), 7.48 (t, J = 7.6 Hz, 1H), 8.23−8.27 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.2, 110.8, 116.0, 120.0, 123.3, 126.3, 129.1, 129.9, 130.3, 131.1, 134.6, 137.1, 137.7, 140.5, 148.1, 155.0 ppm. IR (KBr): 3302, 2904, 1652, 1089, 808, 765 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16ClN2S, 327.0723; found, 327.0716. N-(4-Nitro-2-(p-tolylthio)phenyl)pyridin-2-amine (6e). Purification via silica gel column chromatography (petroleum ether/acetone = 20/1, v/v) afforded 6e as a yellow solid (28 mg, 42% yield). Mp: 147−149 °C. 1 H NMR (400 MHz, CDCl3): δ 2.29 (s, 3H), 6.76 (d, J = 8.0 Hz, 1H), 6.94 (s, 1H), 7.08−7.14 (m, 4H), 7.60 (t, J = 7.6 Hz, 1H), 8.04 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.34 (s, 1H), 8.46 (s, 1H), 8.73 (d, J = 9.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.1, 112.8, 116.1, 117.9, 119.9, 126.6, 128.7, 130.4, 130.5, 132.1, 137.5, 138.1, 140.4, 147.9, 148.1, 153.5 ppm. IR (KBr): 3309, 2906, 1568, 1485, 1083, 806, 748 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16N3O2S, 338.0963; found, 338.0966. N-(4-Methyl-2-(phenylthio)phenyl)pyridin-2-amine (6f). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 6f as a pale-yellow solid (33 mg, 57% yield). Mp: 66−68 °C. 1H NMR (400 MHz, CDCl3): δ 2.30 (s, 3H), 6.68−6.73 (m, 2H), 7.07−7.15 (m, 3H), 7.17−7.26 (m, 4H), 7.37 (s, 1H), 7.40−7.48 (m, 1H), 8.07 (d, J = 8.0 Hz, 1H), 8.20 (s, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 20.7, 110.1, 115.5, 119.4, 120.3, 126.0, 127.5, 129.3, 131.3, 132.0, 136.5, 136.9, 137.6, 140.1, 148.2, 155.5 ppm. IR (KBr): 3327, 2891, 1647, 1139, 829, 754 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17N2S, 293.1112; found, 293.1106. N-(2-(4-Methoxyphenylthio)-4-methylphenyl)pyridin-2-amine (6g). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 15/1, v/v) afforded 6g as a pale-yellow solid (38 mg, 60% yield). Mp: 69−71 °C. 1H NMR (400 MHz, CDCl3): δ 2.27 (s, 3H), 3.75 (s, 3H), 6.67−6.72 (m, 2H), 6.79 (d, J = 8.0 Hz, 2H), 7.09−7.15 (m, 2H), 7.17−7.23 (m, 3H), 7.44 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 8.20 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 20.8, 55.5, 109.6, 115.0, 115.3, 120.3, 124.4, 125.9, 130.1, 131.5, 132.5, 134.8, 137.6, 138.5, 148.2, 155.8, 158.9 ppm. IR (KBr): 3302, 2916, 1683, 1095, 827, 758 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2OS, 323.1218; found, 323.1209. N-(2-(2-Methoxyphenylthio)-4-methylphenyl)pyridin-2-amine (6h). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 15/1, v/v) afforded 6h as a pale-yellow solid 12436

DOI: 10.1021/acs.joc.7b02221 J. Org. Chem. 2017, 82, 12430−12438

Article

The Journal of Organic Chemistry (32 mg, 51% yield). Mp: 79−81 °C. 1H NMR (400 MHz, CDCl3): δ 2.29 (s, 3H), 3.93 (s, 3H), 6.71 (d, J = 6.8 Hz, 2H), 6.75−6.81 (m, 2H), 6.84 (d, J = 8.0 Hz, 1H), 7.07−7.14 (m, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.41−7.48 (m, 2H), 8.11 (d, J = 8.0 Hz, 1H), 8.20 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 20.7, 56.0, 110.4, 110.6, 115.4, 119.0, 119.1, 121.5, 124.8, 127.2, 128.2, 131.4, 131.8, 137.4, 137.5, 140.7, 148.1, 155.5, 156.2 ppm. IR (KBr): 3361, 2918, 1654, 1128, 823, 750 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2OS, 323.1218; found, 323.1211. N-(2-(4-Chlorophenylthio)-4-methylphenyl)pyridin-2-amine (6i). Purification via silica gel column chromatography (petroleum ether/ ethyl acetate = 20/1, v/v) afforded 6i as a orange-red solid (35 mg, 54% yield). Mp: 66−68 °C. 1H NMR (400 MHz, CDCl3): δ 2.30 (s, 3H), 6.69 (d, J = 8.4 Hz, 1H), 6.71−6.77 (m, 1H), 7.03−7.05 (m, 2H), 7.15− 7.17 (m, 3H), 7.22 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.45 (t, J = 8.0 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 20.7, 110.0, 115.7, 119.7, 120.0, 128.7, 129.3, 131.6, 131.9, 132.2, 135.1, 136.9, 137.7, 140.1, 148.2, 155.4 ppm. IR (KBr): 3348, 2906, 1654, 1097, 804, 761 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16ClN2S, 327.0723; found, 327.0713. N-(2-(4-Bromophenylthio)-4-methylphenyl)pyridin-2-amine (6j). Purification via silica gel column chromatography (petroleum ether/ ethyl acetate = 20/1, v/v) afforded 6j as a saffron solid (37 mg, 50% yield). Mp: 86−88 °C. 1H NMR (400 MHz, CDCl3): δ 2.30 (s, 3H), 6.69 (d, J = 8.4 Hz, 1H), 6.72−6.77 (m, 1H), 6.97 (d, J = 8.0 Hz, 2H), 7.18−7.24 (m, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.20 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 20.7, 110.0, 115.7, 117.0, 119.6, 119.7, 128.9, 131.7, 132.22, 132.24, 135.9, 136.9, 137.7, 140.1, 148.2, 155.2 ppm. IR (KBr): 3356, 2924, 1654, 1153, 810, 767, 547 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H16BrN2S, 371.0218; found, 371.0208. N-(2-(2,4-Dichlorophenylthio)phenyl)pyridin-2-amine (6k). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 25/1, v/v) afforded 6k as a flaxen oil (42 mg, 61% yield). 1 H NMR (400 MHz, CDCl3): δ 6.62 (d, J = 8.4 Hz, 1H), 6.75−6.81 (m, 2H), 6.97−7.04 (m, 2H), 7.36 (s, 2H), 7.45−7.52 (m, 2H), 7.56 (d, J = 7.6 Hz, 1H), 8.24 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 111.1, 116.3, 117.0, 118.7, 122.2, 127.8, 128.1, 129.5, 131.8, 131.9, 132.1, 134.6, 137.6, 137.8, 143.4, 148.1, 154.8 ppm. IR (KBr): 3352, 1668, 862, 754, 702, 667 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H13Cl2N2S, 347.0176; found, 347.0171. N-(4-Methyl-2-(methylthio)phenyl)pyridin-2-amine (6l). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 6l as a pale-yellow solid (25 mg, 53% yield). Mp: 77−79 °C. 1H NMR (400 MHz, CDCl3): δ 2.32 (s, 3H), 2.38 (s, 3H), 6.70−6.78 (m, 2H), 6.98 (s, 1H), 7.04 (d, J = 8.0 Hz, 1H), 7.23 (s, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 17.6, 21.0, 108.9, 110.1, 115.2, 120.8, 128.4, 131.5, 133.0, 137.3, 137.7, 148.5, 156.2 ppm. IR (KBr): 3311, 2910, 1647, 1386, 850, 777 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H15N2S, 231.0956; found, 231.0958. N-(4-Methyl-2-(phenylselanyl)phenyl)pyridin-2-amine (6m). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 20/1, v/v) afforded 6m as a yellow oil (48 mg, 70% yield). 1H NMR (400 MHz, CDCl3): δ 2.29 (s, 3H), 6.65 (d, J = 8.0 Hz, 1H), 6.68−6.74 (m, 1H), 7.11 (s, 1H), 7.15−7.22 (m, 4H), 7.27−7.33 (m, 2H), 7.39−7.46 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 8.18 (s, 1H) ppm. 13 C NMR (100 MHz, CDCl3): δ 20.7, 109.6, 115.3, 120.2, 120.5, 126.9, 129.5, 130.8, 130.9, 131.2, 132.7, 137.5, 137.6, 139.5, 148.2, 155.8 ppm. IR (KBr): 3369, 2926, 1652, 819, 765 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H17N2Se, 341.0557; found, 341.0551. 2-(p-Tolylthio)phenol (7).5c Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 40/1, v/v) afforded 7 as a dark and white solid (54 mg, 50% yield). 1H NMR (400 MHz, CDCl3): δ 2.28 (s, 3H), 6.53 (s, 1H), 6.94 (t, J = 7.6 Hz, 1H), 7.00−7.06 (m, 5H), 7.35 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 7.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.1, 115.6, 117.3, 121.3, 127.6, 130.1, 132.1, 132.2, 136.4, 136.8, 157.2 ppm. HRMS (ESI-TOF) m/z: [M − H]− calcd for C13H11OS, 215.0531; found, 215.0532.

4-Methyl-2-(p-tolylthio)aniline (8). Purification via silica gel column chromatography (petroleum ether/ethyl acetate = 40/1, v/v) afforded 8 as a colorless oil (27.5 mg, 60% yield). 1H NMR (400 MHz, CDCl3): δ 2.23 (s, 3H), 2.28 (s, 3H), 4.12 (s, 2H), 6.90 (d, J = 7.6 Hz, 1H), 6.97− 7.07 (m, 5H), 7.26 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 20.4, 21.1, 115.2, 115.6, 127.1, 128.2, 129.9, 131.7, 133.3, 135.5, 137.3, 146.3 ppm. IR (KBr): 3354, 2920, 1388, 804, 765 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H16NS, 230.1003; found, 230.0995. 2-(2-Bromophenylthio)phenol (9). Purification via silica gel column chromatography (petroleum/DCM = 30/1, v/v) afforded 9 as a colorless oil (80 mg, 57% yield). 1H NMR (400 MHz, CDCl3): δ 6.40 (s, 1H), 6.57 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 6.99−7.02 (m, 2H), 7.09−7.13 (m, 2H), 7.41−7.46 (m, 1H), 7.52−7.55 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 115.2, 116.0, 121.1, 121.8, 126.7, 127.1, 128.2, 133.07, 133.09, 137.3, 137.4, 157.7 ppm. IR (KBr): 3628, 1238, 746, 522 cm−1. HRMS (ESI-TOF) m/z: [M − H]− calcd for C12H8OSBr, 278.9479; found, 278.9489. Phenoxathiine (10).19e Purification via silica gel column chromatography (pure hexane) afforded 10 as a white solid (35.4 mg, 62% yield). 1 H NMR (400 MHz, CDCl3): δ 6.98−7.04 (m, 4H), 7.09−7.15 (m, 4H) ppm. 13C NMR (100 MHz, CDCl3): δ 117.9, 120.3, 124.6, 126.9, 127.8, 152.3 ppm. 4-Methyl-2-(p-tolylthio)Pyrido[1,2-a]benzimidazole (11). Purification via silica gel column chromatography (petroleum/ethyl acetate = 3/1, v/v) afforded 11 as a yellow solid (18.2 mg, 60% yield). Mp: 154− 156 °C. 1H NMR (400 MHz, CDCl3): δ 2.36 (s, 3H), 2.44 (s, 3H), 6.78−6.84 (m, 1H), 6.96 (s, 1H), 7.16 (d, J = 6.4 Hz, 2H), 7.34−7.40 (m, 1H), 7.43−7.48 (m, 3H), 7.74 (d, J = 9.2 Hz, 1H), 8.33 (d, J = 6.0 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 21.4, 22.0, 108.2, 110.6, 118.6, 125.2, 126.7, 128.3, 128.6, 129.0, 129.9, 130.2, 131.8, 133.4, 138.0, 141.3, 148.2 ppm. IR (KBr): 2881, 1683, 1384, 881, 756, 702 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H17N2S, 305.1112; found, 305.1108.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02221. Copies of 1H NMR and 13C NMR spectra of key intermediates and final products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yudong Yang: 0000-0002-7142-2249 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grants from the National NSF of China (no. 21502123) and the Comprehensive Training Platform of Specialized Laboratory, College of Chemistry, Sichuan University.

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REFERENCES

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