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. 2018 Sep 27;3(9):12114–12121. doi: 10.1021/acsomega.8b01742

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 ‡, Chan Sik Cho †,*
PMCID: PMC6645425  PMID: 31459288

Abstract

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Quinolin-2(1H)-ones and phenanthridin-6(5H)-ones are synthesized in high yields by K2CO3-promoted cyclization of N-aryl-β-bromo-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 heterocycle-fused hybrid scaffolds exhibit biological and pharmacological properties.1 Besides classical synthetic methods for quinolin-2(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 quinolin-2(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 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, N-aryl-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.

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

Scheme 1

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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 7,8,9,10-tetrahydro analogues under mildly basic conditions, Table 1 shows several attempted results for the lactamization of 2-bromo-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 1,10-phenanthroline.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 1,10-phenanthroline 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 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 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 1. Optimization of Conditions for the Reaction of 1aa.

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entry base (mmol) additive temp (°C) time (h) yieldb (%)
1 K2CO3 (1.5) 1,10-phenanthroline 100 0.5 0
2 K2CO3 (1.5) l-proline 100 0.5 trace
3 K2CO3 (1.5) l-proline 120 0.5 37
4 K2CO3 (1.5) l-proline 150 0.5 59
5 K2CO3 (1.5) l-proline 150 1 69
6 K2CO3 (1.5) l-proline 150 2 88
7 K2CO3 (1.5)   150 0.5 57
8 K2CO3 (1.5)   150 1 72
9 K2CO3 (1.5)   150 2 89
10 K2CO3 (0.3)   150 2 19
11 K2CO3 (0.9)   150 2 63
12 KOH (1.5)   150 2 34
13 Cs2CO3 (1.5)   150 2 34
14 K3PO4 (1.5)   150 2 72
15 KOtBu (1.5)   150 2 90
16c K2CO3 (1.5)   150 24 23
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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.

b

Isolated yield.

c

Under usual heating (screw-capped vial).

Table 2 shows the results for the cyclization of various N-aryl-β-bromo-α,β-unsaturated amides such as N-aryl-2-bromo-1-cycloalkenecarboxamides 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 N-attached 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 2-bromo-N-phenylcyclohex-1-enecarboxamides (1d and 1e) having methyl and phenyl substituents on a cyclohexene ring proceeded likewise to give 7,8,9,10-tetrahydrophenanthridin-6(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 than that when previously described N-aryl-2-bromo-1-cycloalkenecarboxamides were used.

Table 2. Scope of the Cyclization Reactiona.

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a

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.

The present protocol can be extended to the reaction with N-aryl-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-N-phenylbenzamide (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 the para-position to Br, which did not proceed at all toward the cyclization, and the starting material was recovered intact.

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

Scheme 2

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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 employed conditions gave 2a in 68% yield along with the cross-coupled 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.

Scheme 3. Reaction Pathway.

Scheme 3

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Scheme 4. Experiment for the Mechanism Study.

Scheme 4

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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-β-bromo-α,β-unsaturated amides and N-aryl-2-bromobenzamides under microwave irradiation. The present reaction provides a 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-metal-free 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. 1H 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 = 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. 1H 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. 1H 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, 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, DMSO-d6): 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, DMSO-d6): 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); 13C 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.

Acknowledgments

This research was supported by the National Strategic Project-Fine 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).

Supporting Information Available

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)

The authors declare no competing financial interest.

Supplementary Material

ao8b01742_si_001.pdf (10.5MB, pdf)

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