Metal-catalyzed Domino Synthesis of Benzophenanthridines and 6H

Jun 11, 2018 - Palladium(II)/N-Heterocyclic Carbene catalyzed one-pot sequential alpha arylation/alkylation: Access to 3,3-disubstituted oxindoles...
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Cite This: J. Org. Chem. 2018, 83, 8139−8149

Metal-Catalyzed Domino Synthesis of Benzophenanthridines and 6H‑Naphtho[2,3‑c]‑chromenes Baitan Chakraborty, Swapnadeep Jalal, Kartick Paul, Sandip Kundal, and Umasish Jana* Department of Chemistry, Jadavpur University, Kolkata 700 032, West Bengal, India

J. Org. Chem. 2018.83:8139-8149. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 08/17/18. For personal use only.

S Supporting Information *

ABSTRACT: A new and efficient synthesis of tetracyclic phenanthridines and benzo[c]chromenes has been described involving a metal-mediated two-step domino strategy. The first step involved efficient palladium-catalyzed domino carbopalladation/cross coupling, and the second step involved iron-catalyzed domino isomerization/cyclodehydration. The important features of this strategy include high yields, generality, wide substrate scope, and broad functional group tolerance. A plausible mechanism has been proposed to explain the formation of the product.

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INTRODUCTION Natural as well as synthetically produced polycyclic heterocycles are important synthetic targets, owing to their wide abundance in natural products and widespread applications in medicinal chemistry and materials sciences. Therefore, the development of quick, efficient, and versatile methods for the syntheses of new classes of benzo-fused heterocycles is in high demand in the area of medicinal chemistry and materials sciences. For examples, phenanthridine ring systems are significant structural motifs found in a wide variety of naturally occurring phenanthridines and benzophenanthridine alkaloids with extensive pharmacological activities and are of great interest in the field of materials sciences.1 Important compounds in this class include ethidium salts as DNA intercalators as well as fagaronine, nitidine, and trispheridine as promising antitumor agents, which were subjected to clinical trials (Figure 1).2 Looking at such potential therapeutic and materials applications, extensive efforts have been devoted toward the development of new strategies and methods to access large varieties of phenanthridines, benzo[b]phenanthridines, and other annulated forms.3,4 In comparison, the isomeric benzo[j]phenanthridine has been reported for good pharmacological activity, but the synthesis has been less explored.5 Similarly, tricyclic benzo[c]chromene and tetracyclic 6Hnaphtho[2,3-c]chromene skeletons are important structural motifs embedded in numerous natural products and show remarkable biological activities.6 Consequently, numerous synthetic methods have been developed for the synthesis of tricyclic 6H-benzo[c]chromene derivatives,7 whereas the synthesis of tetracyclic 6H-naphtho[2,3-c]chromene skeletons is scarcely reported.8 In addition, most of these synthetic methods can only be applied to furnish the products only with a narrow scope of structural diversity. Therefore, a novel strategy that provides a general and efficient synthetic route to many different benzo[j]phenanthridines and 6H-naphtho[2,3c]chromenes is still highly desirable. © 2018 American Chemical Society

In recent years, the construction of polycyclic heterocycles involving metal-mediated domino reactions has been a powerful tool and has received tremendous attention,9 as it provides step-economic access to furnish structural complexity with great diversity from simple starting materials. In this regard, our group has recently reported a novel two-step strategy involving palladium-catalyzed domino carbon−carbon bond formation and, subsequently, iron-mediated domino isomerization/cyclodehydration for easy access to varieties of benzofused indoles and benzofuran derivatives, under extremely mild conditions.10 In light of this precedence, we envisioned that this strategy could also be useful for the synthesis of very important benzofused quinoline and chromene derivatives from substrate B. We, herein, report a general strategy for the efficient synthesis of both benzo[j]phenanthridine and 6H-naphtho[2,3-c]chromene derivatives C under modified reaction conditions. Our strategy for the synthesis of tetracyclic phenanthridine and benzo[c]chromene derivatives is delineated in the Scheme 1. Compound B can be constructed from compound A via a domino Heck−Suzuki coupling reaction of homopropargylated 2-haloanilide or 2halophenolic ether with 2-formylphenylboronic acid. To the best of our knowledge, this would be the first report for the syntheses of benzophenanthridine and benzo[c]chromene derivatives via a single and efficient strategy.

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RESULTS AND DISCUSSION The required dihydroquinoline derivatives 2 were prepared using our modified domino carbopalladation/Suzuki coupling of 1 (1 equiv) with 2-formylphenylboronic acid (1.5 equiv) in the presence of Pd(PPh3)4 (5 mol %), 2.5 M K2CO3, and toluene/ethanol at 80 °C. A number of substrates were prepared under these conditions; the results are summarized in Scheme 2. This reaction was found to be general for the Received: April 12, 2018 Published: June 11, 2018 8139

DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

Article

The Journal of Organic Chemistry

Figure 1. Some important natural products containing fused phenanthridines and fused benzo[c]chromenes.

Scheme 1. Our Synthetic Strategy for the Tetracyclic Heterocycle

Scheme 2. Preparation of the Substrates 2a

a Reaction conditions: 0.5 mmol of 1, 0.75 mmol of 2-formylphenylboronic acid, 0.01 mmol of Pd(PPh3)4 in 3 mL of an aq 2.5 M K2CO3 solution, 3 mL of ethanol, and 3 mL of toluene at 80 °C under an Ar atmosphere. bYield of the reaction performed at 95 °C.

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DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

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The Journal of Organic Chemistry

mixture was heated to reflux for 3 h (Table 1, entries 2 and 3). Catalyst loading of 5 mol % provided a lower yield of 68% (Table 1, entry 14), and 15 mol % did not improve the results. Solvents such as MeNO2, CH3CN, and chlorobenzene were screened in the presence of Fe(OTf)3 only to find inferior results (Table 1, entries 4−6). We also examined the reaction with different catalysts under similar conditions. Among the metal salts, Cu(OTf)2 (60%), AgOTf (55%), and In(OTf)3 (42%) gave lower yields, whereas FeBr3, SC(OTf)3, and Yb(OTf)3 did not initiate the reaction (Table 1, entries 7−12). These results demonstrated that Fe(OTf)3 exhibited a remarkably higher catalytic activity for this particular transformation compared to other Lewis acids. On the other hand, a strong Brønsted acid such as TfOH (10 mol %) gave a good yield of the desired product in 80% yield (Table 1, entry 13). Hence, the optimum condition that stood out for the isomerization/cycloaromatization reaction is the catalysis of Fe(OTf)3 (10 mol %) in refluxing 1,2-DCE for 3 h. We moved forward with the aforementioned optimal conditions to find the robustness of the synthesis in terms of variation in the substrate. At first, the substrates with substituent R1 at the 2-haloaniline nucleus were tested. Under the optimized reaction conditions, the 2-haloaniline nucleus bearing electron-donating groups such as p-Me and pOMe reacted smoothly and offered excellent yields of 90% and 85%, respectively (Scheme 3, 3b and 3c). The reaction seemed to be a little less expressive toward electron-withdrawing R1 groups. However, on heating at 120 °C in chlorobenzene for a little longer, substrates with p-F and p-Cl groups yielded 67% and 60% of the desired products (Scheme 3, 3d and 3e). Next, we investigated the influence of different substitutions at the olefinic center, which is directly involved in the isomerization process. Strongly electron-donating 4-methoxyphenyl substitution was quite efficient in this position with yields of 80%, 72%, and 75% (Scheme 3, 3j, 3f, 3h), respectively. In the case of aryl groups with a weakly electron-donating group such as pMe and a weakly electron-withdrawing group such as p-Cl, the reactions were sluggish under the optimized conditions. However, the reactions smoothly proceeded in chlorobenzene at 120 °C and gave the desired products in 70% and 58% yields, respectively (Scheme 3, 3g and 3i). Along this line, it is worth mentioning that instead of a tosyl protecting group on nitrogen, the mesyl group also gave an impressive result as well (Scheme 3, 3j). All of the structures of dihydrophenanthridine derivatives were charaterized by NMR spectroscopy and HRMS. The structure of 3b was also confirmed by X-ray diffraction of the single crystal. (See the Supporting Information for the ORTEP diagram and other X-ray crystallography details.) Moreover, this synthetic route can further be extended by one facile step to fabricate the complete aromatic framework of benzo[j]phenanthridine. The detosylation reaction of 5,6dihydrobenzo[j]phenanthridine 3a was carried out in a sealed tube using K2CO3 in ethanol at 100 °C for 6 h to obtain benzo[j]phenanthridine 4a in 80% yield (Scheme 4). Encouraged by the versatility of the Fe(OTf)3-catalyzed isomerization/cycloaromatization strategy, we attempted a new route toward the synthesis of 6H-naphtho[2,3-c]chromene derivatives. Necessary starting materials 6a−6d were prepared following a similar strategy. However, it was observed that better results of Heck−Suzuki coupling of 5 with 2formylphenylboronic acid was obtained in the presence of K3PO4 in 1,4-dioxane with Pd(dppf)2Cl2 (5 mol %) at 65 °C−

preparation of varieties of dihydroquinoline derivatives in good yields in a stereoselective manner via 6-exo-dig cyclization onto the carbon−carbon triple bond. For example, 2-haloaniline derivatives possessing strong electron-donating groups such as Me and OMe and weakly electron-withdrawing groups such as F and Cl (Scheme 2, entries 2b−2e and 2g−2h) underwent smooth Heck−Suzuki coupling under normal reaction conditions in high yields (56−78%). Similarly, different groups on the aryl ring at the alkyne terminus such as Me, OMe, and Cl (Scheme 2, entries 2f−2j) were also compatible and gave the desired products in good yields (60−77%). After preparing the series of substrates, we focused on optimizing the reaction conditions of domino isomerization/ cyclodehydration for the construction of benzo[j]phenanthridine derivative 3a using dihydroquinoline derivative 2a in the presence of various catalysts. The results are summarized in Table 1. We began our probe with anhydrous Table 1. Optimization of the Reaction Conditionsa

entry

catalyst

solvent

temperature (°C)

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

FeCl3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 Fe(OTf)3 FeBr3 Cu(OTf)2 In(OTf)3 AgOTf Sc(OTf)3 Yb(OTf)3 TfOH Fe(OTf)3b

DCE DCE DCE CH3NO2 CH3CN C6H5Cl DCE DCE DCE DCE DCE DCE DCE DCE

reflux rt reflux 85 reflux 85 reflux reflux reflux reflux reflux reflux reflux reflux

time (h) yield (%) 6 6 3 6 6 4 3 6 6 6 6 6 2 3

trace trace 86 40 33 65 0 60 42 55 NR NR 80 68

a Reaction conditions: 0.15 mmol of 2a and 0.015 mmol of catalyst in 1.5 mL of solvent under an Ar atmosphere. bCatalyst load: 0.0075 mmol.

FeCl3 (10 mol %) as a catalyst in 1,2-dichloroethane at room temperature, according to our previous work. Unfortunately, the reaction did not proceed in the presence of FeCl3 (10 mol %) at room temperature; however, heating under reflux for 6 h resulted in the formation of desired 3a in trace amounts. We understood that the driving force for our previous isomerization/cyclodehydration for the preparation of benzofused indole and benzofused benzofuran was complete aromatization, while the expected product in the present study would be partially aromatized 5,6-dihydrobenzo[j]phenanthridine 3a and, hence, less likely to form. Further investigations showed that the said isomerization/cycloaromatization is quite sensitive to a catalyst and the reaction temperature. When the reaction was carried out in the presence of more reactive Fe(OTf)3 (10 mol %) as a catalyst in 1,2-dichloroethane at room temperature, a trace amount of product was obtained, and the yield dramatically improved to 86% when the reaction 8141

DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

Article

The Journal of Organic Chemistry Scheme 3. Substrate Scopes for the Synthesis of 5,6-Dihydrobenzo[j]phenanthridinesa

a

Reaction conditions: 0.15 mmol of 2 and 0.015 mmol of Fe(OTf)3 in 1.5 mL of 1,2-DCE at reflux under an Ar atmosphere. bYields of the reactions performed in 1.5 mL of chlorobenzene at 120 °C under an Ar atmosphere.

(Scheme 6, 7a). Like in the earlier synthesis, electron-rich substrate 6b with a p-methoxyphenyl group at the olefinic center proved to suit well in this case (82%, Scheme 6, 7b). However, substrate 6c, having both a Br and Me group in the phenol part, required heating for 6 h at 115 °C in chlorobenzene to provide a yield of 75% (Scheme 6, 7c). Furthermore, it was observed that the two mutually opposing substituents in the same ring, i.e., OMe and CHO, were well tolerated to furnish the product in 73% yield, although a higher temperature was needed (Scheme 6, 7d). Therefore, it is evident that stereoelectronic factors of the substituents are not that impactful in our synthesis of 6H-naphtho[2,3-c]chromene derivatives. Finally, a plausible mechanism that is similar to our previous work is, hereby, proposed for this reaction as shown in Scheme 7.10 In the first step, the palladium(0) complex would react with substrate 1 via oxidative addition, followed by syncarbopalladation, leading to a σ-alkylpalladium(II) intermediate 1a′ via a 6-exo-dig cyclization process. Next, the intermediate 1a′ would undergo smooth transmetalation with 2-formylphenylboronic acid to furnish intermediate 1b′, with subsequent reductive elimination furnishing product 2. In most of the cases, only syn-product was isolated as a sole product; however, in a few cases, concomitant formation of minor antiisomers resulted due to the isomerization of intermediate 1b′.10c In the second step, the isomerization of product 2 to

Scheme 4. Detosylation of Dihydrobenzo[j]phenanthridine

80 °C to avail a variety of substrates such as 6a−6d in good yields (Scheme 5, 54−78%). Scheme 5. Preparation of Substrate 6

Thereafter, the standardized reaction conditions for the earlier synthesis were successfully employed for the isomerization/cyclodehydration of 6a−6d to scrutinize the generality of this motivated synthesis. It was noticed that, with no substitutions at the phenolic part, or at the olefinic aryl variant, the reaction produced the expected product with 80% yield 8142

DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

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The Journal of Organic Chemistry Scheme 6. Synthesis of Some 6H-Naphtho[2,3-c]chromene Derivativesa

Reaction conditions: 0.15 mmol of 6 and 0.015 mmol of Fe(OTf)3 in 1.5 mL of 1,2-DCE at 70 °C under an Ar atmosphere. bYields of the reactions in 1.5 mL of chlorobenzene at 115 °C.

a

Scheme 7. Proposed Mechanism for Two-Step Domino Synthesis of Tetracyclic Benzofused Heterocycles

2b′ presumably took place through the complexation of the carbonyl group with the Fe(OTf)3. As Fe(OTf)3 has a better polarizing power compared to FeCl3, Fe(OTf)3 worked efficiently for this process. Then, protonation of 2b′ would produce the intermediate 2c′, which on intramolecular Friedel−Crafts alkylation and subsequent aromatization by dehydration of water affords the desired tetracyclic phenanthridine or benzo[c]chromene derivatives 3.

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cyclization strategy that may be exploited in the formation of larger rings and other polycyclic heterocycles in future.

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EXPERIMENTAL SECTION

General. 1H NMR spectra were recorded with a Bruker (300, 400, or 500 MHz) spectrometer as solutions in CDCl3. Chemical shifts are expressed in parts per million (ppm, δ) and are referenced to CDCl3 (δ 7.26 ppm for all of the compounds) as an internal standard. All coupling constants are absolute values and are expressed in Hz. The description of the signals include the following: s = singlet, bs = broad singlet, d = doublet, dd = double doublet, t = triplet, m = multiplet, dt = doublet of triplets, and td = triplet of doublets. 13C NMR spectra were recorded with Bruker 300 (75 MHz) and 500 (125 MHz) spectrometers as solutions in CDCl3 with complete proton decoupling. Chemical shifts are expressed in parts per million (ppm, δ) and are referenced to CHCl3 (δ = 77.0 ppm) as an internal standard. Electrospray ionization technique and TOF mass analyzer were used for HRMS. The routine monitoring of the reaction was performed with silica gel coated glass slides (Merck, silica gel G for TLC), which were analyzed with iodine. Solvents, reagents, and chemicals were purchased from Aldrich, Alfa aeser, Merck, SRL,

CONCLUSION

In summary, we have developed a unique approach for the synthesis of 5,6-dihydrobenzo[j]phenanthridine and 6Hnaphtho[2,3-c]chromene derivatives via a palladium-catalyzed domino Heck−Suzuki reaction and a subsequent ironcatalyzed isomeriztion/cyclodehydration reaction. Apart from being general and atom-economical, mild reaction conditions, high yields, broad substrate scope, and the use of easily available starting materials promote this as a promising 8143

DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

Article

The Journal of Organic Chemistry Spectrochem, and Process Chemicals. All reactions involving moisture-sensitive reactants were executed with oven-dried glassware. Representative Experimental Procedure for the Synthesis and Characterization Data of (Z)-2-(Phenyl(1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)methyl)benzaldehyde (2a). In a round-bottom flask filled with Ar gas, N-(2-bromophenyl)-4-methyl-N-(4-phenylbut3-yn-1-yl)benzenesulfonamide (1a) (227 mg, 0.5 mmol), 2formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) were taken in a mixed solvent of toluene (3 mL) and ethanol (3 mL). The reaction mixture was stirred at 80 °C for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was extracted with ethyl acetate (15 mL, twice); the combined organic layer was washed with water (15 mL, three times), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel (100−200 mesh) column chromatography, eluted by petroleum ether/ethyl acetate (90:10 v/ v), to afford 179 mg of product 2a (75%) as a pale yellow solid, mp 130−132 °C. 1H NMR (CDCl3, 300 MHz): δ 9.97 (s, 1H), 7.81− 7.75 (m, 2H), 7.63 (d, J = 7.8 Hz, 2H), 7.30−7.22 (m, 7H), 7.09 (t, J = 7.8 Hz, 1H), 6.97 (d, J = 6.9 Hz, 2H), 6.69−6.64 (m, 1H), 6.56 (d, J = 6.6 Hz, 1H), 6.24 (d, J = 6.9 Hz, 1H), 3.83 (t, J = 6.0 Hz, 2H), 2.87 (bs, 1H), 2.77 (bs, 1H), 2.45 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.4, 145.8, 143.8, 141.8, 137.8, 136.5, 134.4, 133.6, 132.8, 132.1, 130.2, 129.8, 129.5, 128.9, 128.5, 128.2, 127.6, 127.5, 127.5, 124.3, 124.3, 46.9, 31.4, 21.6. HRMS: calcd for C30H25NO3SNa [M + Na]+, 502.1452; found, 502.1450. (Z)-2-((6-Methyl-1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)(phenyl)methyl)benzaldehyde (2b). N-(2-Iodo-4-methylphenyl)-4methyl-N-(4-phenylbut-3-yn-1-yl)benzenesulfonamide (1b) (259 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were treated similarly to the procedure for the synthesis of 2a for 3 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (90:10 v/v), the desired product 2b (193 mg, 78%) was obtained as a white solid, mp 132−134 °C. 1H NMR (CDCl3, 300 MHz): δ 9.94 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.63 (t, J = 8.1 Hz, 3H), 7.30−7.23 (m, 7H), 6.98−6.88 (m, 3H), 6.30 (d, J = 11.1 Hz, 2H), 3.81 (d, J = 6.6 Hz, 2H), 2.81−2.70 (m, 2H), 2.45 (s, 3H), 1.85 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.5, 146.0, 143.7, 141.9, 136.6, 135.4, 135.3, 134.2, 133.9, 133.6, 132.8, 132.0, 130.8, 130.4, 129.8, 129.7, 129.6, 129.4, 129.0, 128.6, 128.5, 127.5, 127.4, 127.3, 124.4, 122.5, 46.8, 31.4, 21.6, 20.6. HRMS: calcd for C31H27NO3SNa [M + Na]+, 516.1609; found, 516.1610. (Z)-2-((6-Methoxy-1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)(phenyl)methyl)benzaldehyde (2c). N-(2-Iodo-4-methoxyphenyl)-4methyl-N-(4-phenylbut-3-yn-1-yl)benzenesulfonamide (1c) (265 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were treated similarly to the procedure for the synthesis of 2a for 6 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (88:12 v/v), the desired product 2c (147 mg, 58%) was obtained as a yellow solid, mp 151−153 °C. 1H NMR (CDCl3, 300 MHz): δ 9.94 (s, 1H), 7.78−7.75 (m, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 2.7 Hz, 1H), 7.35−7.18 (m, 7H), 6.96 (d, J = 7.8 Hz, 2H), 6.46 (d, J = 8.7 Hz, 1H), 6.38−6.36 (m, 1H), 6.23 (dd, J = 8.7, 2.7 Hz, 1H), 3.87−3.79 (m, 2H), 3,75 (s, 3H), 2.80−2.71 (m, 2H), 2.45 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.6, 159.3, 146.4, 144.0, 142.2, 138.9, 136.5, 134.3, 133.8, 133.7, 132.6, 132.3, 131.2, 129.9, 129.6, 128.8, 128.6, 127.6, 127.4, 122.7, 111.4, 108.8, 55.4, 47.0, 31.2, 21.8. HRMS: calcd for C31H27NO4SNa [M + Na]+, 532.1559; found, 532.1555. (Z)-2-((6-Fluoro-1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)(phenyl)methyl)benzaldehyde (2d). N-(2-Bromo-4-fluorophenyl)-4methyl-N-(4-phenylbut-3-yn-1-yl)benzenesulfonamide (1d) (236 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5

M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were heated at 95 °C similarly to the procedure for the synthesis of 2a for 5 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (90:10 v/v), the desired product 2d (139 mg, 56%) was obtained as an off-white flaky solid. 1 H NMR (CDCl3, 300 MHz): δ 9.91 (s, 1H), 7.80−7.72 (m, 2H), 7.61 (d, J = 7.8 Hz, 3H), 7.36−7.21 (m, 6H), 6.95 (d, J = 7.2 Hz, 2H), 6.84−6.81 (m, 1H), 6.24−6.19 (m, 2H), 3.85−3.79 (m, 2H), 2.85−2.72 (m, 2H), 2.47 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.2, 144.8, 144.0, 141.3, 137.3, 136.4, 134.3, 133.8, 131.7, 131.3, 130.5, 129.8, 129.7, 129.3, 128.5, 128.0, 127.7, 127.6, 126.6, 126.5, 116.4, 116.1, 115.3, 115.0, 46.7, 31.3, 21.7. HRMS: calcd for C30H24FNO3SNa [M + Na]+, 520.1358; found, 520.1359. (Z)-2-((6-Chloro-1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)(phenyl)methyl)benzaldehyde (2e). N-(4-Chloro-2-iodophenyl)-4methyl-N-(4-phenylbut-3-yn-1-yl)benzenesulfonamide (1e) (268 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were treated similarly to the procedure for the synthesis of 2a for 5 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (90:10 v/v), the desired product 2e (161 mg, 63%) was obtained as a pale yellow solid, mp 180−182 °C. 1 H NMR (CDCl3, 300 MHz): δ 9.88 (s, 1H), 7.78−7.70 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.37−7.19 (m, 7H), 7.03−6.94 (m, 3H), 6.45 (d, J = 2.4 Hz, 1H), 6.29 (dd, J = 7.8, 1.2 Hz, 1H), 3.84−3.77 (m, 2H), 2.81−2.70 (m, 2H), 2.44 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.0, 144.7, 144.1, 141.2, 137.0, 136.2, 134.3, 133.7, 132.0, 131.4, 129.8, 129.8, 129.4, 128.4, 128.0, 127.5, 125.4, 46.9, 30.9, 21.6. HRMS: calcd for C30H24ClNO3SNa [M + Na]+, 536.1063; found, 536.1066. (Z)-2-((4-Methoxyphenyl)(1-tosyl-2,3-dihydroquinolin-4(1H)ylidene)methyl)benzaldehyde (2f). N-(2-Bromophenyl)-N-(4-(4methoxyphenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide (1f) (243 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were treated similarly to the procedure for the synthesis of 2a for 7 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (85:15 v/ v), the desired product 2f (154 mg, 60%) was obtained as a pale yellow solid. 1H NMR (CDCl3, 300 MHz): δ 9.97 (s, 1H), 7.77 (t, J = 8.4 Hz, 2H), 7.60 (d, J = 4.5 Hz, 2H), 7.28 (d, J = 8.7 Hz, 3H), 7.20 (td, J = 7.2, 1.5 Hz, 1H), 7.07 (t, J = 7.8 Hz, 1H), 6.90 (dd, J = 6.6, 2.1 Hz, 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.65 (t, J = 7.5 Hz, 1H), 6.55 (dd, J = 7.8, 1.5 Hz, 1H), 6.18 (dd, J = 7.5, 0.9 Hz, 1H), 3.87−3.73 (m, 5H), 2.93−2.89 (m, 1H), 2.80−2.74 (m, 1H), 2.44 (s, 3H). 13 C{1H} NMR (CDCl3, 75 MHz): δ 191.6, 158.9, 146.2, 143.9, 137.7, 136.5, 135.5, 134.6, 134.4, 133.6, 132.2, 131.2, 130.9, 130.3, 129.8, 128.9, 128.0, 127.6, 124.4, 113.9, 55.4, 47.1, 31.6, 21.7. HRMS: calcd for C31H27NO4SNa [M + Na]+, 532.1559; found, 532.1559. (Z)-2-((6-Methyl-1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)(ptolyl)methyl)benzaldehyde (2g). N-(2-Iodo-4-methylphenyl)-4methyl-N-(4-(p-tolyl)but-3-yn-1-yl)benzenesulfonamide (1g) (264 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were treated similarly to the procedure for the synthesis of 2a for 3 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (85:15 v/v), the desired product 2g (196 mg, 77%) was obtained as a greenish white solid. 1H NMR (CDCl3, 300 MHz): δ 9.98 (s, 1H), 7.76 (dd, J = 7.5, 1.8 Hz, 1H), 7.67−7.60 (m, 3H), 7.32−7.21 (m, 4H), 7.09 (d, J = 7.8 Hz, 2H), 6.90−6.84 (m, 3H), 6.31−6.25 (m, 2H), 3.85−3.75 (m, 2H), 2.79 (dt, J = 22.8, 6.6 Hz, 2H), 2.44 (s, 3H), 2.32 (s, 3H), 1.85 (s, 3H). 8144

DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

Article

The Journal of Organic Chemistry C{1H} NMR (CDCl3, 75 MHz): δ 191.6, 146.4, 143.8, 139.2, 137.4, 136.7, 135.5, 135.3, 134.4, 133.9, 133.6, 132.5, 132.1, 130.9, 130.7, 129.8, 129.4, 129.3, 128.9, 128.5, 127.6, 127.5, 124.4, 46.9, 31.6, 21.7, 21.3, 20.7. HRMS: calcd for C32H29NO3SNa [M + Na]+, 530.1765; found, 530.1766. (Z)-2-((4-Methoxyphenyl)(6-methyl-1-tosyl-2,3-dihydroquinolin4(1H)-ylidene)methyl)benzaldehyde (2h). N-(2-Iodo-4-methylphenyl)-N-(4-(4-methoxyphenyl)but-3-yn-1-yl)-4-methylbenzenesulfonamide (1h) (273 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were treated similarly to the procedure for the synthesis of 2a for 5 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (85:15 v/ v), the desired product 2h (157 mg, 60%) was obtained as a greenish semisolid. 1H NMR (CDCl3, 300 MHz): δ 9.95 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 3H), 7.32−7.20 (m, 4H), 6.88 (d, J = 6.9 Hz, 3H), 6.81 (d, J = 8.7 Hz, 2H), 6.30 (s, 1H), 6.22 (d, J = 7.2 Hz, 1H), 3.84−3.79 (m, 5H), 2.85−2.77 (m, 2H), 2.44 (s, 3H), 1.85 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.5, 158.8, 146.4, 143.7, 136.6, 135.2, 135.1, 134.4, 133.8, 133.5, 132.2, 132.0, 130.8, 130.7, 129.7, 128.8, 128.5, 127.6, 127.4, 124.3, 113.8, 55.3, 46.9, 31.5, 21.6, 20.6. HRMS: calcd for C32H29NO4SNa [M + Na]+, 546.1715; found, 546.1714. (Z)-2-((4-Chlorophenyl)(6-methyl-1-tosyl-2,3-dihydroquinolin4(1H)-ylidene)methyl)benzaldehyde (2i). N-(4-(4-Chlorophenyl)but-3-yn-1-yl)-N-(2-iodo-4-methylphenyl)-4-methylbenzenesulfonamide (1i) (274 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were treated similarly to the procedure for the synthesis of 2a for 3.5 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (90:10 v/ v), the desired product 2i (175 mg, 67%) was obtained as a brown semisolid. 1H NMR (CDCl3, 400 MHz): δ 9.92 (s, 1H), 7.78 (d, J = 7.2 Hz, 1H), 7.66−7.61 (m, 3H), 7.37−7.27 (m, 6H), 6.97−6.91 (m, 3H), 6.30 (t, J = 7.2 Hz, 2H), 3.87−3.77 (m, 2H), 2.85−2.72 (m, 2H), 2.46 (s, 3H), 1.87 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.2, 145.3, 143.7, 140.1, 136.6, 135.3, 134.5, 134.3, 134.0, 133.7, 133.3, 133.0, 132.0, 130.9, 130.8, 130.3, 129.7, 129.5, 129.1, 128.7, 127.7, 127.6, 124.4, 46.6, 31.5, 21.6, 20.6. HRMS: calcd for C31H26ClNO3SNa [M + Na]+, 550.1220; found, 550.1224. (Z)-2-((4-Methoxyphenyl)(1-(methylsulfonyl)-2,3-dihydroquinolin-4(1H)-ylidene)methyl)benzaldehyde (2j). N-(2-Bromophenyl)-N(4-(4-methoxyphenyl)but-3-yn-1-yl)methanesulfonamide (1j) (202 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), a 2.5 M aqueous K2CO3 solution (3 mL), and Pd(PPh3)4 (11.5 mg, 0.01 mmol) in a mixed solvent of toluene (3 mL) and ethanol (3 mL) were treated similarly to the procedure for the synthesis of 2a for 4 h. After the completion of reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (80:20 v/v), the desired product 2j (135 mg, 62%) was obtained as a brown semisolid. 1H NMR (CDCl3, 500 MHz): δ 10.16 (s, 1H), 7.77−7.73 (m, 2H), 7.48 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.12−7.06 (m, 3H), 6.88 (d, J = 8.5 Hz, 2H), 6.66 (t, J = 7.5 Hz, 1H), 6.60 (dd, J = 7.5, 1.5 Hz, 1H), 3.95−3.91 (m, 1H), 3.82 (s, 3H), 3.66−3.65 (m, 1H), 3.09−3.07 (m, 1H), 3.00 (s, 3H), 2.85 (m, 1H). 13C{1H} NMR (CDCl3, 125 MHz): δ 191.3, 159.3, 146.1, 138.1, 134.5, 134.4, 134.2, 134.0, 133.8, 132.3, 131.2, 130.6, 129.4, 128.9, 128.7, 127.9, 123.7, 121.6, 114.2, 55.4, 47.3, 37.8, 31.3. HRMS: calcd for C25H23NO4SNa [M + Na]+, 456.1246; found, 456.1248. Representative Experimental Procedure for the Synthesis and Characterization Data of 12-Phenyl-5-tosyl-5,6-dihydrobenzo[j]phenanthridine (3a). In an oven-dried round-bottom flask, (Z)-2(phenyl(1-tosyl-2,3-dihydroquinolin-4(1H)-ylidene)methyl)benzaldehyde (2a) (72 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were added to 1,2-dichloroethane (1.5 mL) under an Ar 13

atmosphere, and the mixture was stirred for 3 h at refluxing conditions. The solvent was evaporated after the completion of reaction (monitored by TLC). The crude reaction mixture was purified by column chromatography on silica gel (100−200 mesh), eluted by petroleum ether/ethyl acetate (90:10 v/v), to afford the desired product 3a (59 mg, 86%) as a white solid, mp 195−197 °C. 1 H NMR (CDCl3, 300 MHz): δ 7.83−7.75 (m, 2H), 7.66 (s, 1H), 7.51−7.29 (m, 6H), 7.22−7.13 (m, 3H), 6.78 (bs, 3H), 6.64−6.55 (m, 3H), 4.99 (s, 2H), 1.86 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 143.2, 139.4, 138.1, 135.6, 132.5, 131.9, 130.6, 130.4, 129.8, 128.7, 128.4, 127.9, 127.8, 127.5, 127.3, 126.7, 126.4, 125.9 125.7, 124.9, 51.8, 20.9. HRMS: calcd for C30H23NO2SNa [M + Na]+, 484.1347; found, 484.1348. 2-Methyl-12-phenyl-5-tosyl-5,6-dihydrobenzo[j]phenanthridine (3b). Substrate 2b (74 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were taken in 1,2-DCE (1.5 mL) and treated similarly to the procedure for the synthesis of compound 3a for 3 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (90:10 v/v), to obtain the desired product 3b (64 mg, 90%) as yellow crystals, mp 213−215 °C. 1H NMR (CDCl3, 300 MHz): δ 7.81 (d, J = 8.1 Hz, 1H), 7.64−7.58 (m, 3H), 7.50−7.31 (m, 5H), 7.12 (d, J = 6.6 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.78 (bs, 2H), 6.54 (d, J = 6.9 Hz, 2H), 6.33 (s, 1H), 4.97 (s, 2H), 1.89 (s, 3H), 1.85 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 143.1, 139.5, 136.3, 135.6, 135.5, 135.2, 132.8, 132.5, 131.9, 130.6, 130.4, 130.1, 128.6, 128.6, 128.4, 127.5, 127.3, 127.2, 126.7, 126.3, 125.9, 124.9, 51.9, 21.1, 20.9. HRMS: calcd for C31H25NO2SNa [M + Na]+, 498.1504; found, 498.1501. 2-Methoxy-12-phenyl-5-tosyl-5,6-dihydrobenzo[j]phenanthridine (3c). Substrate 2c (76 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were taken in 1,2-DCE (1.5 mL) and treated similarly to the procedure for the synthesis of compound 3a for 3 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (90:10 v/v), to obtain the desired product 3c (63 mg, 85%) as a yellow crystalline solid, mp 221−223 °C. 1H NMR (CDCl3, 300 MHz): δ 7.80 (d, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7.48−7.35 (m, 4H), 7.30 (s, 2H), 7.16 (d, J = 7.8 Hz, 2H), 6.78 (s, 2H), 6.57 (d, J = 7.8 Hz, 2H), 6.50 (d, J = 9.0 Hz, 1H), 6.35 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 3.83 (s, 3H), 1.87 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 158.8, 143.2, 139.6, 139.3, 135.5, 135.3, 132.9, 132.1, 131.3, 130.6, 130.4, 128.7, 128.4, 127.5, 127.3, 127.3, 126.5, 126.0, 125.8, 124.8, 123.2, 113.0, 111.9, 55.5, 51.9, 20.9. HRMS: calcd for C31H25NO3SNa [M + Na]+, 514.1453; found, 514.1453. 12-(4-Methoxyphenyl)-5-tosyl-5,6-dihydrobenzo[j]phenanthridine (3f). Substrate 2f (76 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were taken in 1,2-DCE (1.5 mL) and treated similarly to the procedure for the synthesis of compound 3a for 2.5 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (90:10 v/v), to obtain the desired product 3f (53 mg, 72%) as a dark brown solid, mp 167−169 °C. 1H NMR (CDCl3, 300 MHz): δ 7.82− 7.74 (m, 2H), 7.64 (s, 1H), 7.48−7.42 (m, 2H), 7.32 (d, J = 6.9 Hz, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 6.82 (t, J = 7.5 Hz, 1H), 6.68 (d, J = 7.8 Hz, 3H), 6.54 (d, J = 7.8 Hz, 2H), 4.98 (s, 2H), 3.90 (s, 3H), 1.85 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 159.0, 143.1, 138.0, 136.2, 135.6, 133.3, 132.5, 132.0, 131.5, 131.4, 130.8, 129.8, 128.4, 128.0, 127.7, 127.4, 127.3, 126.8, 126.3, 125.8, 125.8, 124.7, 114.1, 55.3, 51.9, 20.9. HRMS: calcd for C31H25NO3SNa [M + Na]+, 514.1453; found, 514.1454. 12-(4-Methoxyphenyl)-2-methyl-5-tosyl-5,6-dihydrobenzo[j]phenanthridine (3h). Substrate 2h (79 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were taken in 1,2-DCE (1.5 mL) and treated similarly to the procedure for the synthesis of compound 3a for 3 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (90:10 v/v), to obtain the desired product 3h (57 mg, 75%) as a moss green solid, mp 198−200 °C. 1H NMR (CDCl3, 300 MHz): δ 7.81 (d, J = 8.1 Hz, 1H), 7.63 (s, 2H), 7.49 (d, J = 7.2 Hz, 2H), 7.38− 8145

DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

Article

The Journal of Organic Chemistry

(CDCl3, 75 MHz): δ 143.0, 137.0, 136.4, 136.4, 135.6, 135.4, 135.2, 132.9, 132.6, 132.5, 131.9, 130.7, 130.5, 130.3, 129.3, 128.5, 128.4, 127.7, 127.5, 127.4, 127.3, 126.8, 126.3, 125.8, 124.7, 52.0, 21.2, 21.1, 20.9. HRMS: calcd for C32H27NO2SNa [M + Na]+, 512.1660; found, 512.1660. 12-(4-Chlorophenyl)-2-methyl-5-tosyl-5,6-dihydrobenzo[j]phenanthridine (3i). Substrate 2i (79 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were taken in chlorobenzene (1.5 mL) and treated similarly to the procedure for the synthesis of compound 3d for 8 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (90:10 v/v), to obtain the desired product 3i (44 mg, 58%) as greenish white crystals. 1H NMR (CDCl3, 400 MHz): δ 7.83 (d, J = 8.4 Hz, 1H), 7.68−7.63 (m, 2H), 7.52−7.48 (m, 1H), 7.40−7.32 (m, 4H), 7.10 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 1H), 6.69 (s, 2H), 6.53 (d, J = 8.0 Hz, 2H), 6.35 (s, 1H), 4.96 (s, 2H), 1.96 (s, 3H), 1.86 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 143.1, 138.0, 135.6, 135.5, 135.4, 134.9, 133.4, 132.6, 132.4, 132.0, 131.9, 130.5, 129.9, 128.8, 128.3, 127.6, 127.5, 126.5, 126.2, 126.1, 125.2, 51.9, 21.1, 20.9. HRMS: calcd for C31H24ClNO2SNa [M + Na]+, 532.1114; found, 532.1117. Scale Synthesis (1 mmol) of the Compound 3i. Substrate 2i (528 mg, 1 mmol) and Fe(OTf)3 (50.3 mg, 0.1 mmol) were taken in chlorobenzene (10 mL) and treated similarly to the procedure for the synthesis of compound 3d for 10 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (90:10 v/v), to obtain the desired product 3i (285 mg, 56%) as greenish white crystals. Experimental Procedure for the Synthesis and Characterization Data of 12-Phenylbenzo[j]phenanthridine (4a). In an oven-dried sealed tube, substrate 3a (46 mg, 0.1 mmol) and K2CO3 (42 mg, 0.3 mmol) were taken in 2 mL of ethanol and heated at 100 °C for 6 h. After the completion of the reaction, the reaction mixture was extracted with dichloromethane (20 mL) and washed with water (20 mL). The combined organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (100−200 mesh), eluted by petroleum ether/ethyl acetate (85:15 v/ v), to obtain the desired product 4a (24 mg, 80%) as a fluorescent green solid, mp 137−139 °C. 1H NMR (CDCl3, 300 MHz): δ 9.38 (s, 1H), 8.64 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.66−7.50 (m, 7H), 7.42−7.33 (m, 3H), 7.16−7.11 (m, 1H). 13 C{1H} NMR (CDCl3, 75 MHz): δ 155.9, 145.3, 141.2, 137.0, 134.8, 131.7, 130.4, 130.1, 129.9, 128.7, 128.3, 128.2, 127.8, 127.6, 127.3, 126.8, 126.4, 126.3, 125.8, 125.0. HRMS: calcd for C23H15NNa [M + Na]+, 328.1102; found, 328.1101. Representative Experimental Procedure for the Synthesis and Characterization Data of (Z)-2-(Chroman-4-ylidene(phenyl)methyl)benzaldehyde (6a). In an oven-dried round-bottom flask filled with Ar gas, 1-iodo-2-((4-phenylbut-3-yn-1-yl)oxy)benzene (5a, 174 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), K3PO4 (318 mg, 1.5 mmol), and Pd(dppf)2Cl2 (8.2 mg, 0.01 mmol) were taken in 1,4-dioxane (5.5 mL). The reaction mixture was stirred at 70 °C for 4 h. After the reaction was complete (monitored by TLC), the reaction mixture was extracted with ethyl acetate (20 mL, twice); the combined organic layer was washed with water (15 mL, three times), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified by silica gel (100−200 mesh) column chromatography, eluted by petroleum ether/ethyl acetate (98:2 v/v), to afford the desired product 6a (116 mg, 72%) as a brown semisolid, along with the inseparable isomer from the Suzuki reaction only. (Almost 10% of 6a yield is calculated using the NMR data.) 1H NMR (CDCl3, 300 MHz): δ 10.26 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.54 (s, 2H), 7.44−7.24 (m, 4H), 7.16 (d, J = 6.9 Hz, 2H), 7.00 (s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.50−6.42 (m, 2H), 4.28 (t, J = 5.4 Hz, 2H), 2.85 (s, 2H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.5, 155.4, 146.4, 142.2, 134.2, 134.1, 132.7, 132.5, 132.1, 130.2, 129.9, 129.4, 128.5, 128.4, 127.9, 127.4, 121.3, 119.5, 117.1, 66.9, 29.3. HRMS: calcd for C23H18O2Na [M + Na]+, 349.1205; found, 349.1205.

7.30 (m, 1H), 7.12 (d, J = 7.5 Hz, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.95 (d, J = 7.8 Hz, 2H), 6.68 (bs, 2H), 6.53 (d, J = 7.5 Hz, 2H), 6.39 (s, 1H), 4.96 (s, 2H), 3.90 (s, 3H), 1.94 (s, 3H), 1.85 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 159.1, 143.0, 136.1, 135.5, 135.4, 135.2, 133.1, 132.5, 131.9, 131.5, 131.2, 130.6, 130.3, 128.5, 128.3, 127.5, 127.3, 126.7, 126.3, 125.8, 124.7, 114.1, 55.5, 52.0, 21.2, 20.9. HRMS: calcd for C32H27NO3SNa [M + Na]+, 528.1610; found, 528.1611. 12-(4-Methoxyphenyl)-5-(methylsulfonyl)-5,6-dihydrobenzo[j]phenanthridine (3j). Substrate 2j (65 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were taken in 1,2-DCE (1.5 mL) and treated similarly to the procedure for the synthesis of compound 3a for 4.5 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (85:15 v/v), to obtain the desired product 3j (50 mg, 80%) as a white crystalline solid, mp 193−195 °C. 1H NMR (CDCl3, 300 MHz): δ 7.89−7.84 (m, 2H), 7.65 (t, J = 8.4 Hz, 2H), 7.54−7.50 (m, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.23−7.18 (m, 1H), 7.12 (d, J = 7.2 Hz, 2H), 7.03 (d, J = 7.5 Hz, 2H), 6.98−6.92 (m, 2H), 4.93 (s, 2H), 3.92 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 159.4, 138.1, 137.6, 133.8, 132.8, 132.6, 131.9, 131.4, 130.7, 130.2, 128.3, 128.1, 127.9, 127.8, 127.3, 127.0, 126.6, 126.5, 124.8, 114.7, 55.5, 51.6, 38.4. HRMS: calcd for C25H21NO3SNa [M + Na]+, 438.1140; found, 438.1140. Representative Experimental Procedure for the Synthesis and Characterization Data of 2-Fluoro-12-phenyl-5-tosyl-5,6dihydrobenzo[j]phenanthridine (3d). In an oven-dried roundbottom flask, (Z)-2-((6-fluoro-1-tosyl-2,3-dihydroquinolin-4(1H)ylidene)(phenyl)methyl)-benzaldehyde (2d) (74 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were added to chlorobenzene (1.5 mL) under an Ar atmosphere, and the mixture was stirred for 5 h at 120 °C. The solvent was evaporated after the completion of reaction (monitored by TLC). The crude reaction mixture was purified by column chromatography on silica gel (100−200 mesh), eluted by petroleum ether/ethyl acetate (90:10 v/v), to afford the desired product 3d (49 mg, 67%) as a greenish yellow solid, mp 185− 187 °C. 1H NMR (CDCl3, 300 MHz): δ 7.83 (d, J = 7.8 Hz, 1H), 7.74−7.68 (m, 2H), 7.53−7.30 (m, 6H), 7.11 (d, J = 7.8 Hz, 2H), 6.93−6.88 (m, 1H), 6.77 (bs, 2H), 6.57 (d, J = 7.8 Hz, 2H), 6.26 (d, J = 11.1 Hz, 1H), 4.99 (s, 2H), 1.88 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 143.3, 138.7, 137.0, 135.3, 133.9, 132.8, 132.7, 131.5, 130.1, 129.6, 129.4, 129.0, 128.5, 127.8, 127.5, 127.3, 126.8, 126.7, 126.1, 125.0, 116.3, 116.0, 115.0, 114.7, 51.8, 20.9. HRMS: calcd for C30H22FNO2SNa [M + Na]+, 502.1253; found, 502.1255. 2-Chloro-12-phenyl-5-tosyl-5,6-dihydrobenzo[j]phenanthridine (3e). Substrate 2e (77 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were taken in chlorobenzene (1.5 mL) and treated similarly to the procedure for the synthesis of compound 3d for 6 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (92:8 v/v), to obtain the desired product 3e (44 mg, 60%) as a brownish solid, mp 190−192 °C. 1H NMR (CDCl3, 300 MHz): δ 7.82 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.53−7.41 (m, 5H), 7.35 (d, J = 7.8 Hz, 1H), 7.17−7.11 (m, 3H), 6.77 (s, 2H), 6.57 (d, J = 7.8 Hz, 2H), 6.50 (s, 1H), 4.97 (s, 2H), 1.86 (s, 3H). 13C{1H} NMR (CDCl3, 125 MHz): δ 143.5, 139.0, 137.2, 136.7, 135.7, 133.0, 132.2, 131.7, 130.3, 129.9, 129.1, 128.7, 128.0, 127.9, 127.6, 127.5, 127.0, 126.9, 126.3, 125.2, 51.9, 21.0. HRMS: calcd for C30H22ClNO2SNa [M + Na]+, 518.0958; found, 518.0957. 2-Methyl-12-(p-tolyl)-5-tosyl-5,6-dihydrobenzo[j]phenanthridine (3g). Substrate 2g (76 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were taken in chlorobenzene (1.5 mL) and treated similarly to the procedure for the synthesis of compound 3d for 8 h. Likewise, the purification of the crude product was done by column chromatography, the eluent being petroleum ether/ethyl acetate (90:10 v/v), to obtain the desired product 3g (52 mg, 70%) as off-white crystals, mp 194−196 °C. 1H NMR (CDCl3, 300 MHz): δ 7.81 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 3.9 Hz, 2H), 7.50−7.43 (m, 3H), 7.31 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 7.8 Hz, 1H), 6.66 (bs, 2H), 6.54 (d, J = 7.8 Hz, 2H), 6.38 (s, 1H), 4.96 (s, 2H), 2.46 (s, 3H), 1.91 (s, 3H), 1.85 (s, 3H). 13C{1H} NMR 8146

DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

Article

The Journal of Organic Chemistry (Z)-2-(Chroman-4-ylidene(4-methoxyphenyl)methyl)benzaldehyde (6b). 1-Iodo-2-((4-(4-methoxyphenyl)but-3-yn-1-yl)oxy)benzene (5b, 189 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), K3PO4 (318 mg, 1.5 mmol), and Pd(dppf)2Cl2 (8.2 mg, 0.01 mmol) were taken in 1,4-dioxane (5.5 mL). The reaction mixture was stirred at 65 °C for 3 h. After the completion of the reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. The crude material was purified by silica gel (100−200 mesh) column chromatography, eluted by petroleum ether/ethyl acetate (95:5 v/v), to afford the desired product 6b (139 mg, 78%) as a pale yellow solid, mp 141− 143 °C. 1H NMR (CDCl3, 300 MHz): δ 10.24 (s, 1H), 7.88 (dd, J = 7.5, 1.5 Hz, 1H), 7.53 (td, J = 7.5, 1.5 Hz, 1H), 7.41 (t, J = 7.52 Hz, 1H), 7.27 (dd, J = 7.5, 1.5 Hz), 7.07 (dd, J = 6.6, 2.1 Hz, 2H), 7.01− 6.96 (m, 1H), 6.86 (dd, J = 6.6, 2.4 Hz, 2H), 6.76 (dd, J = 8.1, 1.2 Hz, 1H), 6.50−6.38 (m, 2H), 4.28 (t, J = 5.7 Hz, 2H), 3.80 (s, 3H), 2.91−2.79 (m, 2H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.7, 158.7, 155.4, 146.9, 134.8, 134.4, 134.3, 133.1, 132.7, 132.0, 131.9, 131.8, 131.5, 130.0, 129.2, 128.5, 127.9, 121.6, 119.6, 117.2, 113.9, 67.0, 55.4, 29.5. HRMS: calcd for C24H20O3Na [M + Na]+, 379.1310; found, 379.1312. (Z)-2-((8-Bromo-6-methylchroman-4-ylidene)(phenyl)methyl)benzaldehyde (6c). 1,3-Dibromo-5-methyl-2-((4-phenylbut-3-yn-1yl)oxy)benzene (5c, 160 mg, 0.41 mmol), 2-formylphenylboronic acid (92 mg, 0.61 mmol), K3PO4 (261 mg, 1.23 mmol), and Pd(dppf)2Cl2 (6.5 mg, 0.008 mmol) in 1,4-dioxane (4.5 mL) were treated similarly to the procedure for the synthesis of 6a for 5 h at 75 °C. After the completion of the reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (97:3 v/v), the desired product 6c (92 mg, 54%) was obtained as a white solid. 1H NMR (CDCl3, 300 MHz): δ 10.24 (s, 1H), 7.90 (d, J = 7.5 Hz, 1H), 7.55 (td, J = 7.5, 1.2 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.37−7.26 (m, 4H), 7.17 (d, J = 7.5 Hz, 2H), 7.10 (s, 1H), 6.21 (s, 1H), 4.39−4.35 (m, 2H), 2.88−2.83 (m, 2H), 1.81 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.3, 149.5, 146.0, 141.8, 134.1, 133.4, 133.3, 132.5, 132.0, 130.1, 129.8, 129.2, 128.6, 128.4, 128.0, 127.6, 122.5, 110.5, 67.7, 29.1, 20.1. HRMS: calcd for C24H19BrO2Na [M + Na]+, 441.0466; found, 441.0465. (Z)-4-((2-Formylphenyl)(p-tolyl)methylene)-5-methoxychroman7-carbaldehyde (6d). 4-Iodo-3-methoxy-5-((4-(p-tolyl)but-3-yn-1yl)oxy)benzaldehyde (5d) (210 mg, 0.5 mmol), 2-formylphenylboronic acid (113 mg, 0.75 mmol), K3PO4 (318 mg, 1.5 mmol), and Pd(dppf)2Cl2 (8.2 mg, 0.01 mmol) in 1,4-dioxane (5.5 mL) were treated similarly to the procedure for the synthesis of 6a for 3 h at 75 °C. After the completion of the reaction, the reaction mixture was also treated likewise up to the purification by column chromatography. Eluting by petroleum ether/ethyl acetate (85:15 v/v), the desired product 6d (138 mg, 69%) was obtained as an off-white solid. 1H NMR (CDCl3, 300 MHz): δ 10.13 (s, 1H), 9.06 (s, 1H), 7.79 (d, J = 7.5 Hz, 1H), 7.50−7.46 (m, 1H), 7.39−7.34 (m, 1H), 7.22−7.18 (m, 2H), 7.09−6.97 (m, 5H), 6.42 (d, J = 1.5 Hz, 1H), 4.44−4.30 (m, 2H), 3.81 (s, 3H), 2.91−2.74 (m, 2H), 2.27 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.2, 190.7, 150.4, 149.4, 145.7, 138.5, 137.9, 134.5, 134.4, 134.4, 132.6, 130.4, 130.1, 129.3, 129.1, 128.8, 128.5, 128.3, 122.0, 107.0, 68.2, 56.2, 28.7, 21.3. HRMS: calcd for C26H22O4Na [M + Na]+, 421.1416; found, 421.1412. Representative Experimental Procedure for the Synthesis and Characterization Data of 12-Phenyl-6H-naphtho[2,3-c]chromene (7a). In an oven-dried round-bottom flask, (Z)-2-(chroman-4ylidene(phenyl)methyl)benzaldehyde (6a) (49 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were added to 1,2-dichloroethane (1.5 mL) under an Ar atmosphere, and the mixture was stirred for 3 h at 70 °C. The solvent was evaporated after the completion of reaction (monitored by TLC). The crude reaction mixture was purified by column chromatography on silica gel (100−200 mesh), eluted by petroleum ether/ethyl acetate (98:2 v/v), to afford the desired product 7a (37 mg, 80%) as a pale yellow solid, mp 138−140 °C. 1H NMR (CDCl3, 300 MHz): δ 7.84 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.55−7.44 (m, 5H), 7.37−7.32 (m, 3H), 7.09 (t, J = 7.2 Hz, 1H),

7.01 (d, J = 7.8 Hz, 1H), 6.71 (d, J = 7.8 Hz, 1H), 6.58 (t, J = 7.2 Hz, 1H), 5.19 (s, 2H). 13C{1H} NMR (CDCl3, 75 MHz): δ 157.2, 139.8, 135.8, 133.6, 132.7, 132.4, 130.7, 129.2, 129.0, 128.7, 127.5, 127.5, 126.9, 126.1, 126.0, 123.8, 123.3, 121.2, 117.5, 70.3. HRMS: calcd for C23H16ONa [M + Na]+, 331.1099; found, 331.1096. 12-(4-Methoxyphenyl)-6H-naphtho[2,3-c]chromene (7b). (Z)-2(Chroman-4-ylidene(4-methoxyphenyl)methyl)benzald-ehyde (6b) (54 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were added to 1,2-dichloroethane (1.5 mL) under an Ar atmosphere, and the mixture was stirred for 2 h at 70 °C. The solvent was evaporated after the completion of reaction. The crude reaction mixture was purified by column chromatography on silica gel (100−200 mesh), eluted by petroleum ether/ethyl acetate (95:5 v/v), to afford the desired product 7b (42 mg, 82%) as a pale yellow solid, mp 131−133 °C. 1H NMR (CDCl3, 300 MHz): δ 7.83 (d, J = 7.8 Hz, 1H), 7.69 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.48−7.44 (m, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.12−7.00 (m, 4H), 6.80 (d, J = 7.8 Hz, 1H), 6.63 (t, J = 7.2 Hz, 1H). 13C{1H} NMR (CDCl3, 75 MHz): δ 159.1, 157.2, 134.0, 132.7, 132.5, 131.9, 131.7, 129.5, 129.2, 128.6, 128.4, 127.5, 126.9, 126.5, 126.0, 125.9, 124.0, 123.3, 123.1, 121.3, 117.5, 114.5, 70.3, 55.4. HRMS: calcd for C24H18O2Na [M + Na]+, 361.1205; found, 361.1207. Representative Experimental Procedure for the Synthesis and Characterization Data of 4-Bromo-2-methyl-12-phenyl-6Hnaphtho[2,3-c]chromene (7c). In an oven-dried round-bottom flask, (Z)-2-((8-bromo-6-methylchroman-4-ylidene)(phenyl)methyl)benzaldehyde (6c) (63 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol) were added to chlorobenzene (1.5 mL) under an Ar atmosphere, and the mixture was stirred for 6 h at 115 °C. The solvent was evaporated after the completion of reaction (monitored by TLC). The crude reaction mixture was purified by column chromatography on silica gel (100−200 mesh), eluted by petroleum ether/ethyl acetate (97:3 v/v), to afford the desired product 7c (45 mg, 75%) as an off-white solid, mp 155−157 °C. 1H NMR (CDCl3, 400 MHz): δ 7.86 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.51−7.47 (m, 4H), 7.40−7.36 (m, 1H), 7.29 (t, J = 3.6 Hz, 2H), 7.16 (s, 1H), 6.39 (s, 1H), 5.24 (s, 2H), 1.88 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 151.6, 139.6, 136.3, 133.5, 132.6, 132.5, 132.2, 131.1, 130.6, 129.4, 129.0, 127.6, 127.0, 126.3, 126.2, 125.9, 124.9, 123.4, 110.9, 70.8, 20.5. HRMS: calcd for C24H17BrONa [M + Na]+, 423.0361; found, 423.0360. 1-Methoxy-12-(p-tolyl)-6H-naphtho[2,3-c]chromene-3-carbaldehyde (7d). Substrate 6d (60 mg, 0.15 mmol) and Fe(OTf)3 (7.5 mg, 0.015 mmol), in 1.5 mL of chlorobenzene, were treated similarly to the procedure for the synthesis of 7c for 5 h. Employing the similar mode of purification, eluent being petroleum ether/ethyl acetate (88:12 v/v), we obtained the desired product 7d (41 mg, 73%) as a white solid, mp 143−145 °C. 1H NMR (CDCl3, 300 MHz): δ 9.21 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.52−7.48 (m, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 3H), 7.18 (d, J = 7.8 hz, 2H), 6.78 (s, 1H), 5.34 (s, 2H), 3.95 (s, 3H), 2.49 (s, 3H). 13C{1H} NMR (CDCl3, 75 MHz): δ 191.4, 152.0, 150.1, 138.0, 136.7, 136.4, 133.8, 132.9, 131.1, 130.5, 130.1, 129.6, 128.4, 127.7, 127.3, 126.7, 126.5, 125.0, 124.5, 123.6, 107.2, 71.0, 56.3, 21.5. HRMS: calcd for C26H20O3Na [M + Na]+, 403.1310; found, 403.1310.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00924. 1

H and

13

C NMR (scanned copies) of the compounds

2a−2j, 3a−3j, 4a, 6a−6d, and 7a−7d and X-ray crystallographic data of the compound 3b (PDF) Crystal data for 3b (CIF) 8147

DOI: 10.1021/acs.joc.8b00924 J. Org. Chem. 2018, 83, 8139−8149

Article

The Journal of Organic Chemistry

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected], [email protected]. ORCID

Umasish Jana: 0000-0002-1583-5129 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS B.C. and S.K. are thankful to the UGC, New Delhi, India, and S.J. and K.P. are thankful to the CSIR, New Delhi, India, for their fellowships.

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