Weak Base-Promoted Lactamization under Microwave Irradiation


Sep 27, 2018 - Weak Base-Promoted Lactamization under Microwave Irradiation: Synthesis of Quinolin-2(1H)-ones and Phenanthridin-6(5H)-ones. Pham Duy ...
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Article Cite This: ACS Omega 2018, 3, 12114−12121

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Weak Base-Promoted Lactamization under Microwave Irradiation: Synthesis of Quinolin-2(1H)‑ones and Phenanthridin-6(5H)‑ones Pham Duy Quang Dao,† Ho-Jin Lim,‡ and Chan Sik Cho*,† †

Department of Applied Chemistry and ‡Department of Environmental Engineering, Kyungpook National University, 80 Daehakro, Bukgu, Daegu 41566, Republic of Korea

ACS Omega 2018.3:12114-12121. Downloaded from pubs.acs.org by 185.252.218.172 on 09/27/18. For personal use only.

S Supporting Information *

ABSTRACT: Quinolin-2(1H)-ones and phenanthridin-6(5H)-ones are synthesized in high yields by K2CO3-promoted cyclization of N-aryl-βbromo-α,β-unsaturated amides and N-aryl-2-bromobenzamides in dimethylformamide under microwave irradiation.



INTRODUCTION It is known that quinolin-2(1H)-ones and their heterocyclefused hybrid scaffolds exhibit biological and pharmacological properties.1 Besides classical synthetic methods for quinolin2(1H)-ones,2 many transition-metal-catalyzed and -free synthetic versions have recently been attempted as alternative methods from the viewpoint of the wide availability of substrates. Several representative examples are shown in Scheme 1. Larock and Jiao reported that N-substituted o-iodoanilines and simple anilines undergo carbonylative cyclization with internal alkynes in the presence of a palladium or rhodium catalyst to give quinolin-2(1H)-ones (Scheme 1, route a).2−4 Inamoto and Doi reported palladium-catalyzed intramolecular amidation of N-tosyl-3,3-diarylacrylamides via C(sp2)−H bond activation for the synthesis of such a scaffold (Scheme 1, route b).5 Such a similar reaction through C−H activation was shown by palladium-catalyzed coupling and cyclization of simple anilines with ethyl acrylates (Scheme 1, route c).6 Fujiwara and Vadola also demonstrated palladium- and gold-catalyzed intramolecular hydroarylation of N-aryl alkynamides leading to quinolin-2(1H)-ones (Scheme 1, route d).7 Acetanilides were found to be coupled and cyclized with propiolates and acrylates in the presence of a ruthenium catalyst along with a carboxylic acid to form quinolin-2(1H)-ones (Scheme 1, route e).8 Such a similar coupling and cyclization was also exemplified by the iridium-catalyzed annulation of N-arylcarbamoyl chlorides with internal alkynes (Scheme 1, route f).9 Wang et al. have shown that α-carbamoyl ketene dithioacetals react with o(trimethylsilyl)phenyl triflate in the presence of a palladium catalyst to give quinolin-2(1H)-ones (Scheme 1, route g).10 In addition to these transition-metal-catalyzed synthetic methods shown in routes a−g of Scheme 1, it is reported that quinolin2(1H)-ones also can be eco-friendly when synthesized by transition-metal-free lactamization of 2-alkenylanilines under carbon dioxide atmosphere in the presence of NaOtBu (Scheme 1, route h).11 Besides the abovementioned representative examples, many other transition-metal-catalyzed and -free © 2018 American Chemical Society

protocols for quinolin-2(1H)-ones have also been developed and documented.12 In connection with this report, as part of our ongoing studies on cyclization reactions,13 we recently reported that aryl 2-bromobenzoates and their analogues are readily cyclized by microwave irradiation to afford 6H-benzo[c]chromen-6-ones and their analogues, respectively.14 The present work arose during the course of application of such a cyclization protocol to the reaction with amide analogues, Naryl-β-bromo-α,β-unsaturated amides. Herein, this report provides transition-metal-free microwave-assisted lactamization of such starting amides leading to quinolin-2(1H)-ones and phenanthridin-6(5H)-ones under mildly basic conditions.



RESULTS AND DISCUSSION On the basis of our recent report on microwave-assisted lactonization of aryl 2-bromobenzoates and their analogues leading to 6H-benzo[c]chromen-6-ones and their 7,8,9,10tetrahydro analogues under mildly basic conditions, Table 1 shows several attempted results for the lactamization of 2bromo-N-phenylcyclohex-1-enecarboxamide (1a), leading to 7,8,9,10-tetrahydrophenanthridin-6(5H)-one (2a).14 It is known that N-aryl-2-halobenzamides are readily cyclized into phenanthridinones under KOtBu and a catalytic amount of 1,10phenanthroline.15 However, treatment of 1a in dimethylformamide (DMF) at 100 °C for 0.5 h in the presence of K2CO3 (5 equiv) along with 1,10-phenanthroline under microwave irradiation (100 W of initial power) did not afford 2a at all, and 1a was recovered almost completely (Table 1, entry 1). No cyclized product 2a was also observed with changing 1,10phenanthroline to L-proline (Table 1, entry 2). The reaction temperature was critical for the formation of 2a, and the yield of 2a increased with the increase in temperature up to 150 °C (Table 1, entries 2−4). Prolonging the reaction time up to 2 h Received: July 22, 2018 Accepted: September 13, 2018 Published: September 27, 2018 12114

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Scheme 1. Representative Synthetic Routes for Quinolin-2(1H)-ones

Table 1. Optimization of Conditions for the Reaction of 1aa

entry

base (mmol)

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

K2CO3 (1.5) K2CO3 (1.5) K2CO3 (1.5) K2CO3 (1.5) K2CO3 (1.5) K2CO3 (1.5) K2CO3 (1.5) K2CO3 (1.5) K2CO3 (1.5) K2CO3 (0.3) K2CO3 (0.9) KOH (1.5) Cs2CO3 (1.5) K3PO4 (1.5) KOtBu (1.5) K2CO3 (1.5)

14 15 16c

additive 1,10-phenanthroline L-proline L-proline L-proline L-proline L-proline

temp (°C)

time (h)

yieldb (%)

100 100 120 150 150 150 150 150 150 150 150 150 150

0.5 0.5 0.5 0.5 1 2 0.5 1 2 2 2 2 2

0 trace 37 59 69 88 57 72 89 19 63 34 34

150 150 150

2 2 24

72 90 23

yield of 2a was generally lower than that with the use of K2CO3 except for KOtBu, which exhibited a similar activity as K2CO3 (Table 1, entries 12−15). A weak base is of great advantage to a strong base in terms of tolerance for functional groups in an organic transformation. Treatment of 1a under usual heating for 24 h at 150 °C afforded 2a in only 23% yield (Table 1, entry 16). As a result, K2CO3 was shown to be the base of choice and inductively coupled plasma-atomic emission spectroscopy analysis of commercial K2CO3 showed ND (Not Detected, below method detection limit, 5−10 ppm) of transition metals such as Co, Cu, Ni, Fe, and Pd. Table 2 shows the results for the cyclization of various N-arylβ-bromo-α,β-unsaturated amides such as N-aryl-2-bromo-1cycloalkenecarboxamides and N-aryl-3-bromoacrylamides under the optimized conditions. The amides (1b and 1c) having a methyl group at para- and ortho-positions to N on the Nattached phenyl ring were also cyclized to give the corresponding 7,8,9,10-tetrahydrophenanthridin-6(5H)-ones (2b and 2c) selectively in similar yields. The cyclization of 2bromo-N-phenylcyclohex-1-enecarboxamides (1d and 1e) having methyl and phenyl substituents on a cyclohexene ring proceeded likewise to give 7,8,9,10-tetrahydrophenanthridin6(5H)-ones (2d and 2e), irrespective of the presence of such substituents on 1d and 1e. From the reaction of the amides (1f− i) having various ring sizes, the corresponding cyclized products 2f−i were also formed in the range of 74−86% yields. For testing the effect of the position of bromide and carbamoyl groups on benzo-fused amides, 1j and 1k were employed. The cyclization took place irrespective of the position. As is the case for the lactonization of benzo-fused phenyl 2-bromocyclohex-1-enecarboxylates, in the reaction with 1k, in addition to the expected product 2k, benzo[i]phenanthridin-5(6H)-one (2k′) was produced by dehydrogenation of the initially formed 2k and/ or initial dehydrogenation of the starting 1k followed by cyclization under the employed conditions.14 Such a similar dehydrogenation was observed in our recent reports on transition-metal-catalyzed and -free cyclization reactions.13a,16 A similar treatment of 3-bromo-N-phenylacrylamides 1l−o under the employed conditions also afforded the corresponding quinolin-2(1H)-ones 2l−o, and the product yield was lower

a Reaction conditions: 1a (0.3 mmol), additive (0.09 mmol), and DMF (3 mL), under microwave irradiation (100 W of initial power) and N2, unless otherwise stated. bIsolated yield. cUnder usual heating (screw-capped vial).

was needed for the effective formation of 2a with complete conversion of 1a (Table 1, entries 4−6). As is the case for the lactonization of aryl 2-bromobenzoates and their analogues, the reaction also proceeded in the absence of a ligand (Table 1, entries 7−9). During the same period of reaction time, the yield of 2a increased from 57% (60% conv of 1a) and 72% (81% conv of 1a) to 89% (100% conv of 1a). A lower yield of 2a and conversion of 1a were observed with a lower amount of K2CO3 (Table 1, entries 10 and 11). The reaction also proceeded using other bases such as KOH, Cs2CO3, K3PO4, and KOtBu, but the 12115

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Table 2. Scope of the Cyclization Reactiona

Reaction conditions: 1 (0.3 mmol), K2CO3 (1.5 mmol), DMF (3 mL), 150 °C, and 2 h, under microwave irradiation (100 W of initial power) and N2.

a

than that when previously described N-aryl-2-bromo-1-cycloalkenecarboxamides were used. The present protocol can be extended to the reaction with Naryl-2-bromobenzamides, which eventually leads to phenanthridin-6(5H)-ones. Phenanthridin-6(5H)-ones are naturally occurring scaffolds and exhibit a wide spectrum of biological activities.17 Many transition-metal-catalyzed and -free synthetic methods have been attempted for the construction of such scaffolds, and several representative synthetic routes are shown in Scheme 2 (routes a−h).17,18 Treatment of 2-bromo-Nphenylbenzamide (1p) under the optimized conditions shown in Table 1 afforded phenanthridin-6(5H)-one (2p) in 85% yield. With N-aryl-2-bromobenzamides (1q and 1r) having the methyl

group at para- and ortho-positions to N on the N-attached phenyl ring, the cyclized products (2q and 2r) were selectively formed in similar yields as observed in the reaction with 1b and 1c. From the reaction of 2-bromo-N-m-tolylbenzamide (1s), the corresponding cyclized products were obtained as a regioisomeric mixture (2s and 2s′), and the molar ratio was calculated by the integration of clearly separated methyl signals in the 1H NMR spectrum.18a 2-Bromo-N-phenylbenzamides (1t and 1u) having methyl and methoxy substituents on the bromoaryl moiety are also cyclized to give the corresponding phenanthridin-6(5H)-ones (2t and 2u). Not shown in Table 2 is the reaction of 2-bromo-5-fluoro-N-phenylbenzamide having F at 12116

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Scheme 2. Representative Synthetic Routes for Phenanthridin-6(5H)-ones

Scheme 3. Reaction Pathway

Scheme 4. Experiment for the Mechanism Study

employed conditions gave 2a in 68% yield along with the crosscoupled product 5a (14% yield) and biphenyl (6) (5% yield) (Scheme 4). A similar treatment of o-methyl substituted amide 1v with 4 afforded the cross-coupled product 5b in 61% yield along with 6 (6% yield). As reported in similar KOtBu-mediated radical cyclizations, the formation of 5a or 5b indicates that the present reaction proceeds via a radical pathway.

the para-position to Br, which did not proceed at all toward the cyclization, and the starting material was recovered intact. As to the reaction pathway, although it is not yet fully understood, this seems to proceed via an initial K2CO3-induced single-electron transfer to produce 3 and subsequent 6-exo/ endo-trig homolytic aromatic substitution (route a) in preference to a 5-exo-trig ipso mode (route b, Scheme 3).14 When the reaction was carried out with the addition of radical scavengers such as 2,2,6,6-(tetramethylpiperidin-1-yl)oxyl, galvinoxyl, or 2,6-di-tert-butyl-4-methylphenol (equimolar amount to 1a) under the employed conditions, 2a was formed in only 15−29% yields. This experimental observation supports evidence for the radical pathway. A similar radical pathway has been proposed by us and others.14,15,19 We confirmed that treatment of 1a with 2 equiv of iodobenzene (4) under the



CONCLUSIONS In summary, we have developed a transition-metal-free synthetic method for quinolin-2(1H)-ones and phenanthridin-6(5H)ones by K2CO3-promoted radical cyclization of N-aryl-βbromo-α,β-unsaturated amides and N-aryl-2-bromobenzamides under microwave irradiation. The present reaction provides a 12117

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= 7.3 Hz, 1H), 7.41−7.44 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6): δ 21.5, 24.9, 27.5, 29.6, 31.9, 115.1, 119.4, 121.5, 123.3, 127.6, 128.9, 136.8, 142.3, 161.6. HRMS (EI): Anal. Calcd for C14H15NO (M+), 213.1154; found, 213.1153. 8-Phenyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (2e). Rf = 0.48. White solid (67 mg, 81%). mp 305−307 °C. 1H NMR (500 MHz, DMSO-d6): δ 1.87−1.97 (m, 1H), 2.08−2.14 (m, 1H), 2.36−2.46 (m, 1H), 2.88−2.95 (m, 3H), 3.05−3.10 (m, 1H), 7.18−7.21 (m, 1H), 7.22−7.25 (m, 1H), 7.31−7.36 (m, 5H), 7.44−7.47 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H), 11.65 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 25.5, 28.5, 30.7, 31.5, 115.1, 119.3, 121.6, 123.4, 126.2, 126.8, 127.6, 128.4, 129.0, 136.9, 142.3, 146.0, 161.4. HRMS (EI): Anal. Calcd for C19H17NO (M+), 275.1310; found, 275.1307. 1,2,3,5-Tetrahydro-4H-cyclopenta[c]quinolin-4-one (2f).22 Rf = 0.45. White solid (43 mg, 78%). mp 259−262 °C. 1H NMR (500 MHz, DMSO-d6): δ 2.09−2.16 (m, 2H), 2.82−2.89 (m, 4H), 7.20−7.23 (m, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.46−7.49 (m, 1H), 7.71 (d, J = 7.7 Hz, 1H), 11.64 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 23.0, 29.7, 34.6, 115.3, 119.0, 121.6, 124.0, 129.2, 133.3, 137.6, 149.5, 161.4. 5,7,8,9,10,11-Hexahydro-6H-cyclohepta[c]quinolin-6-one (2g).23 Rf = 0.46. White solid (55 mg, 86%). mp 269−272 °C. 1 H NMR (500 MHz, DMSO-d6): δ 1.44−1.48 (m, 2H), 1.55− 1.59 (m, 2H), 1.82−1.86 (m, 2H), 2.86−2.88 (m, 2H), 3.00− 3.02 (m, 2H), 7.14−7.17 (m, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.41−7.46 (m, 1H), 7.82 (d, J = 8.1 Hz, 1H), 11.63 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 24.9, 25.2, 25.7, 27.2, 31.7, 115.3, 119.0, 121.6, 123.9, 129.2, 133.3, 137.6, 149.4, 161.3. 7,8,9,10,11,12-Hexahydrocycloocta[c]quinolin-6(5H)-one (2h).24 Rf = 0.46. White solid (55 mg, 81%). mp 265−268 °C. 1 H NMR (500 MHz, DMSO-d6): δ 1.26−1.31 (m, 2H), 1.42− 1.46 (m, 2H), 1.55−1.59 (m, 2H), 1.70−1.74 (m, 2H), 2.77− 2.79 (m, 2H), 3.04−3.06 (m, 2H), 7.14−7.18 (m, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.40−7.43 (m, 1H), 7.74 (d, J = 8.1 Hz, 1H), 11.60 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 24.9, 25.5, 25.8, 26.7, 29.1, 29.7, 115.3, 118.6, 121.6, 124.2, 129.0, 131.5, 137.7, 145.7, 161.1. 7,8,9,10,11,12,13,14,15,16-Decahydrocyclododeca[c]quinolin-6(5H)-one (2i). Rf = 0.48. White solid (63 mg, 74%). mp 276−278 °C. 1H NMR (500 MHz, DMSO-d6): δ 1.16−1.22 (m, 2H), 1.24−1.41 (m, 10H), 1.52−1.63 (m, 4H), 2.29−2.33 (m, 2H), 2.40−2.43 (m, 2H), 7.05−7.08 (m, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.31−7.34 (m, 1H), 7.56 (d, J = 7.7 Hz, 1H), 11.49 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 21.9, 22.9, 23.9, 24.0, 25.3, 25.6, 25.8, 25.9, 26.3, 29.2, 115.5, 119.0, 122.0, 123.7, 127.7, 129.6, 137.6, 141.9, 163.0. HRMS (EI): Anal. Calcd for C19H25NO (M+), 283.1936; found, 283.1939. 7,8-Dihydrobenzo[k]phenanthridin-6(5H)-one (2j).25 Rf = 0.51. White solid (62 mg, 83%). mp 246−248 °C. 1H NMR (500 MHz, DMSO-d6): δ 2.84−2.87 (m, 2H), 3.03−3.06 (m, 2H), 7.23−7.26 (m, 3H), 7.27−7.29 (m, 1H), 7.35 (dd, J = 8.2, 1.0 Hz, 1H), 7.50−7.54 (m, 1H), 7.93 (d, J = 7.5 Hz, 1H), 8.65− 8.67 (m, 1H), 11.88 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 23.5, 27.0, 115.1, 118.6, 121.9, 123.4, 124.6, 125.9, 127.0, 127.3, 127.5, 130.2, 131.6, 136.5, 137.8, 145.8, 160.2. 11,12-Dihydrobenzo[i]phenanthridin-5(6H)-one (2k). Rf = 0.58. White solid (46 mg, 62%). mp 241−243 °C. 1H NMR (500 MHz, DMSO-d6): δ 2.83−2.86 (m, 2H), 3.02−3.05 (m, 2H), 7.20−7.25 (m, 3H), 7.26−7.29 (m, 1H), 7.35 (dd, J = 8.2, 1.0 Hz, 1H), 7.49−7.52 (m, 1H), 7.92 (dd, J = 8.2, 0.9 Hz, 1H), 8.66−8.67 (m, 1H), 11.88 (s, 1H); 13C NMR (125 MHz,

new synthetic approach for such lactam scaffolds, and a continuous study of synthetic applications for carbo- and heterocycles using such a weak base-promoted transition-metalfree cyclization under microwave irradiation is in progress.



EXPERIMENTAL PROCEDURES General. 1H NMR (500 MHz) and 13C NMR (125 MHz) spectra were recorded in DMSO-d6 or CDCl3. The melting points were measured with a Stanford Research Inc. MPA100 automated melting point apparatus. The high-resolution mass spectrometry (HRMS) data were recorded using electronic ionization (EI, magnetic sector-electric sector double focusing mass analyzer) at Korea Basic Science Center (Daegu). Microwave reactions (CEM, Discover LabMate) were performed in a 5 mL sealed tube, and the reaction temperature was maintained by an external infrared sensor. The desired products were separated by thin-layer (a glass plate coated with Kieselgel 60 GF254, Merck) chromatography (TLC). The amides 1 were synthesized from the corresponding carboxylic acids by subsequent treatment of oxalyl chloride and anilines.15,18n Commercially available reagents were used without further purification. General Procedure for the Synthesis of 2. To a 5 mL microwave reaction tube was added 1 (0.3 mmol), K2CO3 (0.208 g, 1.5 mmol), and DMF (3 mL). After stirring at room temperature for 5 min followed by flushing with N2 and sealing the tube, the reaction mixture was stirred at 150 °C for 2 h by microwave irradiation at 100 W initial power. The mixture was cooled to room temperature and filtered through a short silica gel column (dichloromethane/MeOH = 8:2) to eliminate inorganic salts. Evaporation of the solvent under reduced pressure gave a crude mixture, which was separated by TLC (dichloromethane/MeOH = 97:3) to afford 2. Spectroscopic data for all lactams are shown below. 7,8,9,10-Tetrahydrophenanthridin-6(5H)-one (2a).20 Rf = 0.51. White solid (53 mg, 89%). mp 270−273 °C. 1H NMR (500 MHz, DMSO-d6): δ 1.68−1.73 (m, 2H), 1.76−1.80 (m, 2H), 2.44−2.47 (m, 2H), 2.79−2.82 (m, 2H), 7.14−7.17 (m, 1H), 7.28 (d, J = 7.5 Hz, 1H), 7.40−7.43 (m, 1H), 7.65 (d, J = 7.7 Hz, 1H), 11.58 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 21.4, 21.5, 23.5, 24.8, 115.1, 119.5, 121.5, 123.1, 128.0, 128.8, 136.8, 142.6, 161.6. 2-Methyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (2b).21 Rf = 0.56. White solid (59 mg, 92%). mp 287−290 °C. 1 H NMR (500 MHz, DMSO-d6): δ 1.66−1.71 (m, 2H), 1.72− 1.77 (m, 2H), 2.29 (s, 3H), 2.45−2.48 (m, 2H), 2.64−2.67 (m, 2H), 7.07 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.4, 1.6 Hz, 1H), 7.42 (s, 1H), 11.58 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 20.7, 21.0, 21.2, 23.7, 24.8, 116.0, 119.5, 122.7, 123.2, 130.8, 133.1, 134.7, 135.8, 161.6. 4-Methyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (2c).21 Rf = 0.57. White solid (56 mg, 87%). mp 293−295 °C. 1H NMR (500 MHz, DMSO-d6): δ 1.74−1.79 (m, 2H), 1.80−1.85 (m, 2H), 2.41 (s, 3H), 2.54−2.57 (m, 2H), 2.73−2.75 (m, 2H), 7.10−7.13 (m, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 11.60 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 16.9, 20.8, 20.9, 23.4, 24.6, 119.2, 120.1, 122.7, 122.8, 125.3, 130.9, 132.3, 134.5, 161.2. 8-Methyl-7,8,9,10-tetrahydrophenanthridin-6(5H)-one (2d). Rf = 0.55. White solid (58 mg, 90%). mp 278−281 °C. 1H NMR (500 MHz, DMSO-d6): δ 1.05 (d, J = 6.6 Hz, 3H), 1.30− 1.38 (m, 1H), 1.70−1.77 (m, 1H), 1.90−1.95 (m, 2H), 2.68− 2.79 (m, 2H), 2.95−3.01 (m, 1H), 7.15−7.18 (m, 1H), 7.28 (d, J 12118

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DMSO-d6): δ 23.5, 27.0, 115.1, 118.6, 121.9, 123.4, 124.6, 125.9, 127.0, 127.3, 127.5, 130.2, 131.6, 136.6, 137.8, 145.9, 160.2. HRMS (EI): Anal. Calcd for C17H13NO (M+), 247.0997; found, 247.0996. Benzo[i]phenanthridin-5(6H)-one (2k′). Rf = 0.58. White solid (16 mg, 21%). mp 289−291 °C. 1H NMR (500 MHz, DMSO-d6): δ 7.31−7.33 (m, 1H), 7.47 (dd, J = 8.2, 1.1 Hz, 1H), 7.54−7.59 (m, 2H), 7.67−7.70 (m, 1H), 7.73−7.77 (m, 1H), 8.10 (dd, J = 8.0, 1.4 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.56 (d, J = 7.8 Hz, 1H), 10.24 (d, J = 8.7 Hz, 1H), 11.99 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 115.5, 117.5, 119.1, 120.4, 122.2, 124.1, 126.2, 126.7, 127.2, 128.2, 128.5, 130.1, 132.6, 134.0, 135.7, 136.9, 162.1. HRMS (EI): Anal. Calcd for C17H11NO (M+), 245.0841; found, 245.0839. 4-Phenylquinolin-2(1H)-one (2l).12h Rf = 0.41. White solid (44 mg, 67%). mp 234−236 °C. 1H NMR (500 MHz, DMSOd6): δ 6.91 (s, 1H), 7.15−7.18 (m, 1H), 7.28 (d, J = 7.3 Hz, 1H), 7.41−7.44 (m, 1H), 7.60−7.71 (m, 5H), 7.77 (d, J = 8.0 Hz, 1H), 12.87 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 116.7, 119.6, 120.7, 122.5, 126.9, 128.5, 128.8, 130.6, 137.2, 139.0, 153.5, 164.3. 3-Methyl-4-phenylquinolin-2(1H)-one (2m). Rf = 0.42. White solid (50 mg, 71%). mp 243−245 °C. 1H NMR (500 MHz, DMSO-d6): δ 2.01 (s, 3H), 7.02 (dd, J = 8.0, 1.5 Hz, 1H), 7.12−7.16 (m, 1H), 7.24−7.27 (m, 2H), 7.38 (dd, J = 8.3, 1.1 Hz, 1H), 7.45−7.52 (m, 2H), 7.53−7.56 (m, 2H), 11.34 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 22.1, 114.9, 119.1, 121.4, 123.2, 127.9, 128.5, 128.8, 128.9, 129.5, 136.7, 142.1, 145.8, 161.2. HRMS (EI): Anal. Calcd for C16H13NO (M+), 235.0997; found, 235.0095. 3-Butyl-4-phenylquinolin-2(1H)-one (2n). Rf = 0.48. White solid (60 mg, 72%). mp 249−251 °C. 1H NMR (500 MHz, DMSO-d6): δ 0.79 (t, J = 7.4 Hz, 3H), 1.19−1.30 (m, 2H), 1.42−1.48 (m, 2H), 2.42−2.45 (m, 2H), 7.14−7.17 (m, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.31−7.35 (m, 2H), 7.41−7.45 (m, 1H), 7.48−7.54 (m, 3H), 7.82 (d, J = 8.1 Hz, 1H), 11.43 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 13.6, 22.3, 28.9, 33.4, 113.9, 118.8, 120.4, 122.8, 128.0, 128.2, 128.5, 128.8, 129.2, 135.0, 142.1, 145.4, 160.9. HRMS (EI): Anal. Calcd for C19H19NO (M+), 277.1467; found, 277.1469. 3,4-Diphenylquinolin-2(1H)-one (2o). Rf = 0.53. White solid (67 mg, 75%). mp 277−279 °C. 1H NMR (500 MHz, DMSOd6): δ 7.24−7.26 (m, 4H), 7.29−7.31 (m, 3H), 7.32−7.36 (m, 2H), 7.41−7.44 (m, 3H), 7.56 (dd, J = 8.3, 0.8 Hz, 1H), 7.64− 7.67 (m, 1H), 11.25 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 117.2, 121.0, 122.0, 124.6, 127.4, 128.1, 128.2, 128.3, 128.7, 128.8, 129.8, 131.0, 131.9, 134.3, 134.9, 152.0, 161.7. HRMS (EI): Anal. Calcd for C21H15NO (M+), 297.1154; found, 297.1156. Phenanthridin-6(5H)-one (2p).15 Rf = 0.58. White solid (mg, 85%). mp 306−309 °C. 1H NMR (500 MHz, DMSO-d6): δ 7.22−7.29 (m, 1H), 7.32−7.40 (m, 1H), 7.44−7.52 (m, 1H), 7.61−7.68 (m, 1H), 7.80−7.88 (m, 1H), 8.33 (dd, J = 8.0, 1.5 Hz, 1H), 8.41 (d, J = 8.1 Hz, 1H), 8.44−8.54 (m, 1H), 11.69 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 116.1, 117.6, 122.3, 122.6, 123.3, 125.7, 127.5, 127.9, 129.6, 132.8, 134.3, 136.6, 160.8. 2-Methylphenanthridin-6(5H)-one (2q).18m Rf = 0.52. White solid (56 mg, 89%). mp 255−259 °C. 1H NMR (500 MHz, DMSO-d6): δ 2.41 (s, 3H), 7.28−7.32 (m, 2H), 7.58− 7.61 (m, 1H), 7.82−7.86 (m, 1H), 8.18 (s, 1H), 8.32 (dd, J = 7.9, 0.9 Hz, 1H), 8.47 (d, J = 8.1 Hz, 1H), 11.59 (s, 1H); 13C

NMR (125 MHz, DMSO-d6): δ 20.7, 116.0, 117.2, 122.3, 123.1, 125.5, 127.3, 127.7, 130.1, 130.9, 132.5, 134.3, 134.4, 160.7. 4-Methylphenanthridin-6(5H)-one (2r).18m Rf = 0.53. White solid (52 mg, 83%). mp 237−240 °C. 1H NMR (500 MHz, DMSO-d6): δ 2.51 (s, 3H), 7.20 (t, J = 7.7 Hz, 1H), 7.38−7.40 (m, 1H), 7.62−7.65 (m, 1H), 7.86−7.89 (m, 1H), 8.27−8.29 (m, 1H), 8.35 (d, J = 8.1 Hz, 1H), 8.52−8.54 (m, 1H), 10.76 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 17.3, 117.7, 121.3, 122.4, 122.9, 124.5, 125.3, 127.5, 128.0, 131.1, 133.1, 134.6, 135.0, 161.2. 8,9-Dimethoxyphenanthridin-6(5H)-one (2t).15 Rf = 0.52. White solid (60 mg, 78%). mp 292−294 °C. 1H NMR (500 MHz, DMSO-d6): δ 3.91 (s, 3H), 4.03 (s, 3H), 7.24 (d, J = 7.5 Hz, 1H), 7.33−7.36 (m, 1H), 7.42−7.45 (m, 1H), 7.73 (s, 1H), 7.89 (s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 11.58 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 56.0, 56.6, 104.7, 108.4, 116.4, 118.0, 119.8, 122.5, 123.5, 129.1, 129.8, 136.6, 149.8, 153.7, 160.9. 9-Methylphenanthridin-6(5H)-one (2u).18a Rf = 0.56. White solid (42 mg, 67%). mp 249−251 °C. 1H NMR (500 MHz, DMSO-d6): δ 2.53 (s, 3H), 7.24−7.27 (m, 1H), 7.33−7.37 (m, 1H), 7.45−7.50 (m, 2H), 8.21 (d, J = 8.1 Hz, 1H), 8.31 (s, 1H), 8.36 (dd, J = 8.0, 1.0 Hz, 1H), 11.57 (s, 1H); 13C NMR (125 MHz, DMSO-d6): δ 21.6, 116.1, 117.6, 122.0, 122.5, 123.2, 123.4, 127.5, 129.1, 129.5, 134.3, 136.7, 143.0, 160.9. Experimental Procedure for the Mechanism Study. To a 5 mL microwave reaction tube was added 1a or 1v (0.3 mmol), 4 (0.122 g, 0.6 mmol), K2CO3 (0.208 g, 1.5 mmol), and DMF (3 mL). After stirring at room temperature for 5 min followed by flushing with N2 and sealing the tube, the reaction mixture was stirred at 150 °C for 2 h by microwave irradiation at 100 W initial power. The mixture was cooled to room temperature and filtered through a short silica gel column (ethyl acetate) to eliminate inorganic salts. Evaporation of the solvent under reduced pressure gave a crude mixture, which was separated by TLC (hexane/ethyl acetate = 2:1) to afford 5. N-Phenyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carboxamide (5a). Rf = 0.63. Pale yellow solid (12 mg, 14%). mp 97−99 °C. 1H NMR (500 MHz, CDCl3): δ 1.68−1.73 (m, 2H), 1.76− 1.80 (m, 2H), 2.44−2.47 (m, 2H), 2.80−2.82 (m, 2H), 6.66 (s, 1H), 6.98−7.00 (m, 2H), 7.02−7.05 (m, 1H), 7.16−7.20 (m, 2H), 7.29−7.36 (m, 3H), 7.46−7.48 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 22.1, 23.7, 28.6, 35.4, 120.0, 124.8, 127.9, 128.5, 128.8, 128.9, 129.5, 136.2, 136.9, 139.5, 165.9. HRMS (EI): Anal. Calcd for C19H19NO (M+), 277.1467; found, 277.1469. N-(2,6-Dimethylphenyl)-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-carboxamide (5b). Rf = 0.57. Pale yellow solid (56 mg, 61%). mp 115−117 °C. 1H NMR (500 MHz, CDCl3): δ 1.69− 1.73 (m, 2H), 1.76−1.81 (m, 2H), 2.30 (s, 6H), 2.46−2.49 (m, 2H), 2.80−2.82 (m, 2H), 6.80 (s, 1H), 7.08−7.10 (m, 2H), 7.11−7.17 (m, 3H), 7.50−7.53 (m, 2H), 7.56−7.59 (m, 1H); 13 C NMR (125 MHz, CDCl3): δ 18.8, 21.5, 24.2, 29.8, 36.4, 118.8, 120.7, 127.4, 127.5, 128.27, 128.31, 130.1, 134.5, 135.6, 135.7, 167.4. HRMS (EI): Anal. Calcd for C21H23NO (M+), 305.1780; found, 305.1781.



ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01742. Copies of 1H and 13C NMR spectra of all products (PDF) 12119

DOI: 10.1021/acsomega.8b01742 ACS Omega 2018, 3, 12114−12121

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Pham Duy Quang Dao: 0000-0002-2537-1874 Chan Sik Cho: 0000-0001-6416-1741 Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS This research was supported by the National Strategic ProjectFine Particle of the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT), the Ministry of Environment (ME), and the Ministry of Health and Welfare (MOHW) (2017M3D8A1090658).



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DOI: 10.1021/acsomega.8b01742 ACS Omega 2018, 3, 12114−12121