Copper-Catalyzed Cyclization for Access to 6H-Chromeno[4,3-b

Aug 8, 2017 - ... Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, People's...
59 downloads 10 Views 957KB Size
Download PDF
Article pubs.acs.org/joc

Copper-Catalyzed Cyclization for Access to 6H‑Chromeno[4,3‑b]quinolin-6-ones Employing DMF as the Carbon Source Yiyi Weng, Hao Zhou, Chen Sun, Yuanyuan Xie,* and Weike Su* Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China S Supporting Information *

ABSTRACT: The first example of the copper-catalyzed cyclization of 4-(phenylamino)-2H-chromen-2-ones employing the N-methyl moiety of DMF as the source of the methine (CH) group has been developed, providing an efficient synthetic pathway to access novel functionalized 6Hchromeno[4,3-b]quinolin-6-ones in moderate to good yields.

■

transformations, such as the formylation,14 amination,15 cyanation,16 and methylation17 reactions in terms of costefficiency and step economy. To the best of our knowledge, employing the N-methyl moiety of DMF as a source of a onecarbon synthon was not reported until 2014. In 2014, Xue and Xiao18 first reported Rh-catalyzed direct methylation of ketones. Then Lei19 developed Cu-catalyzed direct oxidative C(sp3)−H methylenation of arylketones in the same year. In 2015, Das20 presented Pd/Ag-catalyzed carbonylation of C(sp2)−H bonds using atmospheric O2 (Scheme 1a). However, employing the methyl group of DMF as the source of the methine group (CH) in the cyclization reaction was not reported until the elegant works by Zhao21a and Liu21b (Scheme 1b). These two methods disclosed the novel synthesis of symmetrical 2,3,5,6-tetrasubstituted pyridines using DMF as the methine group source, respectively. However, construction of unsymmetrical heterocyclic compounds cannot be accomplished by these two strategies. Herein we report a simple and highly efficient protocol for construction of 6H-chromeno[4,3b]quinolin-6-one employing DMF as the methine group source via aerobic copper-catalyzed cyclization of 4-arylaminocoumarins (Scheme 1c). To our knowledge, the application of DMF as the methine group source in transition-metal-catalyzed cyclization for the synthesis of the quinoline skeleton has not been demonstrated thus far.

INTRODUCTION The quinoline scaffold is prevalent in a variety of bioactive and natural compounds.1,2 The quinolines possess useful pharmacological and biological activities including antimicrobial,3 antimalaria,4 antidepressant,5 and anticancer activities.6 Chromeno-quinoline derivatives with a 2H-chromen-2-one ring and a 2H-chromene ring fused to quinoline ring exhibit remarkable properties, such as anticancer activities7,8 and fluorescent pH sensors and estrogen receptor β-selective ligands functions.9,10 The reported routes for preparation of 6H-chromeno[4,3b]quinolin-6-ones usually empolyed Vilsmeier reagent or the formyl group of benzaldehydes as the main source to generate the methine (CH) group in the quinoline ring. In 1987, Tabakovic and co-workers11 reported the traditional strategies for preparation of 6H-chromeno[4,3-b]quinolin-6-ones from 4arylaminocoumarins using Vilsmeier reagent (POCl3/DMF) as the formylation reagent. However, the toxicity and the environmental impact of POCl3 limited the application of this process. Then Wu and co-workers12 developed a method for preparation of 6H-chromeno[4,3-b]quinolin-6-ones, employing 4-chloro-2-oxo-2H-chromene-3-carbaldehyde and aryl isocyanides as substrates, but this method suffered from narrow substrate scope. In 2014, Yao13 developed a protocol of Fe/ AcOH-mediated one-pot synthesis of 6H-chromeno[4,3-b]quinolin-6-ones, which required excessive Fe/AcOH (5 equiv) as reductive reagents. Recently, Sashidhara group reported that molecular iodine could be successfully used to catalyze a onepot tandem annulation of 4-hydroxycoumarin, aromatic aldehydes, and aromatic amines under MW irradiation, affording 6H-chromeno[4,3-b]quinolin-6-ones.7 Hence, it is highly desirable to develop novel, efficient, and environmentfriendly methylation reagents for the construction of 6Hchromeno[4,3-b]quinolin-6-ones with a cheap and robust catalytic system. As one of the most inexpensive and abundant industrial raw materials and solvents, N,N-dimethylformamide (DMF) is considered to be a multipurpose, versatile synthon in organic © 2017 American Chemical Society

■

RESULTS AND DISCUSSION To validate our hypothesis, we initiated our studies with 4-((4bromophenyl)amino)-2H-chromen-2-one (1a) as the model substrate. A positive result was obtained using Cu(OAc)2·H2O as catalyst, TBPB as oxidant, and KOAc as base in DMF, providing the desired 9-bromo-6H-chromeno[4,3-b]quinolin-6one (2a) in 16% yield. Neither O2, Na2S2O8, nor TBHP as Received: June 19, 2017 Published: August 8, 2017 9047

DOI: 10.1021/acs.joc.7b01515 J. Org. Chem. 2017, 82, 9047−9053

Article

The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa,b

Scheme 1. Employing the N-Methyl Group of DMF as Carbon Source

entry

catalyst

oxidant

additive

yield (%)b

1 2 3 4 5c 6c 7c,d 8c 9c,e 10c 11c,f 12c,g

Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O Cu(OAc)2·H2O CuCl Cu(OAc)2·H2O − Cu(OAc)2·H2O Cu(OAc)2·H2O

TBPB O2 TBHP Na2S2O8 TBPB TBPB TBPB TBPB TBPB TBPB TBPB TBPB

− − − − − NaHSO3 NaHSO3 NaHSO3 NaHSO3 NaHSO3 NaHSO3 NaHSO3

16 0 trace 16 28 80 78 72 48 0 58 60

a

Conditions: 0.2 mmol of 1a in the presence of [Cu] (15 mol %), oxidant (3.0 equiv), KOAc (1.0 equiv), and NaHSO3 (1.2 equiv) in 3.5 mL of DMF under 150 °C conditions for 24 h, O2 ballon. bIsolated yield based on 1a. c1a, catalyst, oxidant, base, and additive with novel addition sequence (for details, see the typical procedure for the preparation of 2a). dNaHSO3 (2.0 equiv). eCu(OAc)2·H2O (10 mol %). fTBPB (2.0 equiv). gWithout KOAc. TBHP = tert-butyl hydroperoxide. TBPB = tert-butyl perbenzoate.

slight decrease in yield was observed by switching Br to Cl (2g) or F (2h). Pleasingly, naphthyl and tetrahydronaphthalene moieties were also tolerated, leading to the corresponding products (2m and 2n) in 63% and 56% yields, respectively. Next, the screening of the substitution effect on the coumarin moiety of 4-(phenylamino)-2H-chromen-2-ones was conducted. It was observed that in all cases tested, the corresponding products (2o, 2p, 2q) were isolated in 70%− 75% yields. Finally, substrates with substituents on both the aniline ring and chromen-2-one ring underwent reactions smoothly to yield the targeted products in moderate yields (2r, 2s, and 2t). To gain insight into the mechanism of the reaction, we designed a set of parallel experiments to confirm whether the carbon source is from N-methyl or formyl moiety of DMF. To clarify this, different amides were employed to test this notable transformation (Table 3). As expected, N,N-dimethylacetamide and N,N-dimethylaniline gave rise to the desired product with relatively low yields (53% and 46%), while no conversion was observed using N,N-diethylformamide. All these factors indicated that the CH group of the cyclization product should be from the methyl group on DMF. Based on the above experiments and previous literature,22 a possible mechanism for the synthesis of 6H-chromeno[4,3-b]quinolin-6-ones from 1 is proposed (Scheme 2). Initially, the nucleophilic addition of 1 to the iminium intermediate A which is presumably generated from DMF in the presence of Cu(OAc)2·H2O/TBPB proceeds through a radical pathway. Second, reaction of substrate 1 and intermediated A afford intermediate B. After releasing of one molecule of MeNHCHO, the resulting intermediate D is attacked by NaHSO3, followed by an intramolecular cyclization to generate a dihydropyridine intermediate F (Scheme 2, path a).21a On the other hand, intermediate D experiencing the sequential 6π electrocyclization could also convert into F

oxidants afforded better yields of 2a (Table 1, entries 2−4). We envisioned that changing the addition sequence might increase the reaction yield, considering the potential complexation of copper catalysts with the arylamines. To our delight, the yield of 2a was increased from 16% to 28% as expected (entry 5, for details, see the typical procedure for the preparation of 2a). A significant improvement was achieved by adding NaHSO3 to the reaction mixture, and the yield was dramatically increased up to 80% (entry 6). Notably, the reaction could also proceed smoothly by using CuCl as the catalyst instead of Cu(OAc)2· H2O, albeit with decreased yield (72%, entry 8). Either decreasing the loading of TBPB or Cu(OAc)2·H2O afforded the lower yields (entries 9−11). There was no desired product detected in the absence of Cu(OAc)2·H2O, which proved it was essential for this transformation. Conducting the reaction in the absence of KOAc also decreased the yield (60%, entries 12). With the optimal conditions identified, the scope and generality of the reaction were investigated, and the results are summarized in Table 2. Both substrates with electrondonating (2c−f, 2j, 2k, 2l) and electron-withdrawing (2h and 2i) groups on the aniline ring proceeded smoothly and afforded the desired products in moderate to good yields. It was noted that the substitution position of aryl moieties had little effect on this reaction. An ortho- and para-substituted aniline ring afforded 2c and 2d, respectively, in similar yields. Moreover, a 9048

DOI: 10.1021/acs.joc.7b01515 J. Org. Chem. 2017, 82, 9047−9053

Article

The Journal of Organic Chemistry Table 2. Cu-Catalyzed Cyclization of 4-(Phenylamino)-2H-chromen-2-ones with DMFa

Conditions: 1 (0.2 mmol), Cu(OAc)2·H2O (15 mol %), TBPB (3.0 equiv), NaHSO3 (1.2 equiv), KOAc (1.0 equiv), DMF (3.5 mL), 150 °C, 24 h, O2 ballon with novel addition sequence. Isolated yields based on 1. a

group source, giving the corresponding derivatives in moderate to good yields (56−81%). The mechanism investigation implies that the carbon added is from the methyl group of DMF. With the inexpensive metal catalyst, economical reagent DMF, easy availability of the substrates, and excellent functional group tolerability, we envision this protocol could complete with current methods employing DMF as a source of the one-carbon synthon. This protocol is also recognized as an inexpensive and green route for the synthesis of chromeno-quinoline derivatives.

Table 3. Control Experiments and the Reaction Mechanism Studiesa

■

EXPERIMENTAL SECTION

General Information. All commercial materials were used as received unless otherwise noted. Commercially available chemicals were obtained from Energy Chemical, TCI, Alfa Aesar, and J&K. 1H NMR spectra were recorded at 400, 500, and 600 MHz using TMS as internal standard, 13C NMR spectra were recorded at 100, 125, and 150 MHz using TMS as internal standard. The multiplicities are reported as follows: singlet (s), doublet (d), doublet of doublets (dd), multiplet (m), triplet (t), and broad resonances (br). Mass spectroscopy data of the products were collected on an HRMS-TOF instrument. General Procedure for the Preparation of Starting Materials 1. A mixture of 4-hydroxy-2H-chromen-2-ones (1 mmol) and anilines (3 mmol, 3 equiv) (without solvent) in a 10 mL flask was heated at 180 °C for 2−4 h. After being cooled to room temperature, the reaction mixture was washed with methanol (5 mL) at 60 °C for 0.5 h and then filtered to give the pure products 1. 4-((4-Bromophenyl)amino)-2H-chromen-2-one (1a). Yellow solid, yield: 239 mg, 76%, mp 299.6−300.2 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.22 (dd, J = 8.0, 1.0 Hz, 1H), 7.68−7.64 (m, 3H), 7.44−7.34 (m, 4H), 5.38 (s, 1H). 13C NMR (150 MHz,

Conditions: 1a (0.2 mmol), Cu(OAc)2·H2O (15 mol %), TBPB (3.0 equiv), NaHSO3 (1.2 equiv), KOAc (1.0 equiv), analogues of DMF (3.5 mL), 150 °C, 24 h, O2 ballon with novel addition sequence (SI). Isolated yields based on 1b. a

(Scheme 2, path b).21b Finally, aromatization of F under oxidative conditions affords the desired product 2. Obviously, nucleophilic substitution by NaHSO3 and then the intramolecular cyclization step (path a) could occur prior to 6π electrocyclization step (path b) in this reaction (see Table 1, entries 5 and 6).

■

CONCLUSION In summary, an efficient approach for the synthesis of 6Hchromeno[4,3-b]quinolin-6-ones by Cu-catalyzed oxidative cyclization has been developed using DMF as the methine 9049

DOI: 10.1021/acs.joc.7b01515 J. Org. Chem. 2017, 82, 9047−9053

Article

The Journal of Organic Chemistry Scheme 2. Plausible Reaction Mechanism

DMSO-d6) δ 161.8, 153.8, 152.4, 138.2, 132.9, 132.8, 127.3, 124.1, 123.3, 118.3, 117.5, 114.9, 85.6. MS (ESI): m/z = 316.4 [M + H]+. HRMS-ESI: calcd for C15H10BrNNaO2 [M + Na]+: 337.9787; found: 337.9794. 4-(Phenylamino)-2H-chromen-2-one (1b). Yellow solid, yield: 216 mg, 91%, mp 267.5−268.3 °C (lit.11 267−268 °C). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.26 (d, J = 7.2 Hz, 1H), 7.65−7.63 (m, 1H), 7.50−7.46 (m, 2H), 7.41−7.36 (m, 4H), 7.29 (t, J = 7.6 Hz, 1H), 5.30 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ 161.1, 153.1, 152.1, 137.9, 132.0, 129.2, 125.7, 124.8, 123.3, 122.6, 116.8, 114.3, 84.2. MS (ESI): m/z = 238.4 [M + H]+. HRMS-ESI: calcd for C15H11NNaO2 [M + Na]+: 260.0682; found: 260.0688. 4-(p-Tolylamino)-2H-chromen-2-one (1c). Yellow solid, yield: 206 mg, 82%, mp 273.4−274.0 °C (lit.11 279−280 °C). 1H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.41−7.37 (m, 2H), 7.31−7.26 (m, 4H), 5.23 (s, 1H), 2.35 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 161.9, 153.9, 153.2, 136.0, 135.9, 132.8, 130.5, 125.7, 124.0, 123.2, 117.5, 115.0, 84.4, 21.1. MS (ESI): m/z = 252.3 [M + H]+. HRMS-ESI: calcd for C16H13NNaO2 [M + Na]+: 274.0838; found: 274.0848. 4-((4-Ethylphenyl)amino)-2H-chromen-2-one (1d). Yellow solid, yield: 188 mg, 71%, mp 235.1−235.5 °C. 1H NMR (600 MHz, DMSO-d6) 9.28 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.68−7.65 (m, 1H), 7.42−7.37 (m, 2H), 7.34−7.28 (m, 4H), 5.25 (s, 1H), 2.67 (q, J = 7.8 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ 161.9, 153.9, 153.1, 142.2, 136.2, 132.8, 129.3, 125.7, 124.0, 123.2, 117.5, 115.0, 84.5, 28.2, 16.0. MS (ESI): m/z = 266.2 [M + H]+. HRMS-ESI: calcd for C17H15NNaO2 [M + Na]+: 288.0995; found: 288.0997. 4-((4-Methoxyphenyl)amino)-2H-chromen-2-one (1e). Yellow solid, yield: 179 mg, 67%, mp 240.0−240.3 °C (lit.11 245−246 °C). 1 H NMR (500 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.25−8.23 (m, 1H), 7.68−7.64 (m, 1H), 7.41−7.37 (m, 2H), 7.31−7.29 (m, 2H), 7.10− 7.05 (m, 2H), 5.11 (s, 1H), 3.81 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.6, 157.6, 153.4, 153.3, 132.4, 130.6, 127.2, 123.6, 122.7, 117.1, 114.8, 114.5, 83.6, 55.4. MS (ESI): m/z = 268.2 [M + H]+. HRMS-ESI: calcd for C16H13NNaO3 [M + Na]+: 290.0788; found: 290.0791.

4-((4-Ethoxyphenyl)amino)-2H-chromen-2-one (1f). Yellow solid, yield: 208 mg, 74%, mp 230.1−230.5 °C (lit.11 218−220 °C). 1H NMR (500 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.23−8.22 (m, 1H), 7.66−7.63 (m, 1H), 7.40−7.35 (m, 2H), 7.28−7.25 (m, 2H), 7.04− 7.01 (m, 2H), 5.09 (s, 1H), 4.07 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.5, 156.8, 153.4, 153.2, 132.3, 130.5, 127.2, 123.6, 122.7, 117.0, 115.2, 114.5, 83.5, 63.3, 14.7. MS (ESI): m/z = 282.2 [M + H]+. HRMS-ESI: calcd for C17H15NNaO3 [M + Na]+: 304.0944; found: 304.0941. 4-((4-Chlorophenyl)amino)-2H-chromen-2-one (1g). Yellow solid, yield: 222 mg, 82%, mp 301.2−302.2 °C (lit.11 306 °C). 1H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.21 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.41−7.36 (m, 4H), 5.34 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ 160.7, 152.9, 151.7, 137.0, 131.8, 129.4, 128.9, 126.0, 123.1, 122.3, 116.5, 114.1, 85.0. MS (ESI): m/z = 272.3 [M + H]+. HRMS-ESI: calcd for C15H10ClNNaO2 [M + Na]+: 294.0292; found: 294.0301. 4-((4-Fluorophenyl)amino)-2H-chromen-2-one (1h). Yellow solid, yield: 168 mg, 66%, mp 275.3−276.3 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.23−8.22 (m, 1H), 7.68−7.65 (m, 1H), 7.44−7.37 (m, 4H), 7.35−7.31 (m, 2H), 5.20 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 161.9, 160.4 (JC−F = 243.2 Hz), 153.8, 153.3, 134.9 (JC−F = 2.7 Hz), 132.9, 128.0 (JC−F = 8.6 Hz), 124.1, 123.2, 117.5, 116.8 (JC−F = 22.6 Hz), 114.9, 84.7. MS (ESI): m/z = 256.2 [M + H]+. HRMS-ESI: calcd for C15H10FNNaO2 [M + Na]+: 278.0588; found: 278.0595. Ethyl 4-((2-Oxo-2H-chromen-4-yl)amino)benzoate (1i). White solid, yield: 226 mg, 73%, mp 238.8−239.2 °C. 1H NMR (600 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.25−8.24 (m, 1H), 8.05 (d, J = 6.0 Hz, 2H), 7.70−7.67 (m, 1H), 7.55 (d, J = 12.0 Hz, 2H), 7.44−7.41 (m, 2H), 5.68 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.34 (t, J = 6.0 Hz, 3H). 13C NMR (150 MHz, DMSO-d6) δ 165.7, 161.8, 153.9, 151.6, 143.8, 133.0, 131.1, 126.3, 124.2, 123.5, 123.5, 117.5, 115.1, 87.5, 61.1, 14.7. MS (ESI): m/z = 310.2 [M + H]+. HRMS-ESI: calcd for C18H15NNaO4 [M + Na]+: 332.0893; found: 332.0896. 4-(o-Tolylamino)-2H-chromen-2-one (1j). Yellow solid, yield: 211 mg, 84%, mp 221.8−222.5 °C (lit.11 214−216 °C). 1H NMR (600 MHz, DMSO-d6) 9.25 (s, 1H), 8.28−8.26 (m, 1H), 7.69−7.66 (m, 1H), 7.43−7.29 (m, 2H), 4.61 (s, 1H), 2.21 (s, 3H). 13C NMR (150 9050

DOI: 10.1021/acs.joc.7b01515 J. Org. Chem. 2017, 82, 9047−9053

Article

The Journal of Organic Chemistry MHz, DMSO-d6) δ 161.9, 153.9, 153.7, 136.7, 135.8, 132.8, 131.7, 128.5, 128.2, 127.7, 124.1, 123.2, 117.6, 114.7, 84.0, 17.7. MS (ESI): m/z = 252.2 [M + H]+. HRMS-ESI: calcd for C16H13NNaO2 [M + Na]+: 274.0838; found: 274.0833. 4-((2-Methoxyphenyl)amino)-2H-chromen-2-one (1k). Yellow solid, yield: 163 mg, 61%, mp 224.4−225.1 °C (lit.11 223−225 °C). 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.25(d, J = 7.6 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.39−7.29 (m, 4H), 7.21 (d, J = 8.0 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H), 4.71 (s, 1H), 3.79 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 161.2, 154.3, 153.0, 152.9, 132.0, 128.5, 128.2, 125.6, 123.4, 122.6, 120.8, 116.8, 114.3, 112.5, 83.9, 55.6. MS (ESI): m/z = 268.2 [M + H]+. HRMS-ESI: calcd for C16H13NNaO3 [M + Na]+: 290.0788; found: 290.0797. 4-((2,4-Dimethylphenyl)amino)-2H-chromen-2-one (1l). Yellow solid, yield: 196 mg, 74%, mp 246.3−247.8 °C. 1H NMR (600 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.27−8.26 (m, 1H), 7.68−7.65 (m, 1H), 7.42−7.37 (m, 2H), 7.23 (s, 1H), 7.17−7.14 (m, 2H), 4.60 (s, 1H), 2.34 (s, 3H), 2.16 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 161.9, 153.9, 153.9, 137.5, 135.5, 134.0, 132.8, 132.2, 128.3, 128.2, 124.1, 123.2, 117.5, 114.8, 83.8, 21.1, 17.6. MS (ESI): m/z = 266.2 [M + H]+. HRMS-ESI: calcd for C17H15NNaO2 [M + Na]+: 288.0995; found: 288.0990. 4-(Naphthalen-1-ylamino)-2H-chromen-2-one (1m). Yellow solid, yield: 181 mg, 63%, mp 259.1−260.0 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.45−8.43 (m, 1H), 8.08 (d, J = 10.0 Hz, 1H), 8.04 (s, J = 10.0 Hz, 1H), 7.88 (d, J = 10.0 Hz, 1H), 7.73− 7.69 (m, 1H), 7.68−7.65 (m, 1H), 7.63−7.56 (m, 3H), 7.49−7.46 (m, 1H), 7.43−7.41 (m, 1H), 4.57 (s, 1H). 13C NMR (125 MHz, DMSOd6) δ 161.8, 154.7, 153.9, 134.7, 134.4, 132.9, 129.9, 129.0, 128.4, 127.4, 127.2, 126.6, 126.0, 124.2, 123.4, 123.3, 117.6, 114.8, 85.1. MS (ESI): m/z = 288.2 [M + H]+. HRMS-ESI: calcd for C19H13NNaO2 [M + Na]+: 310.0838; found: 310.0849. 4-((5,6,7,8-Tetrahydronaphthalen-1-yl)amino)-2H-chromen-2one (1n). Yellow solid, yield: 236 mg, 81%, mp 211.8−212.3 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.13 (s, 1H), 8.27−8.25 (m, 1H), 7.67−7.64 (m, 1H), 7.42−7.37 (m, 2H), 7.24 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 4.63 (s, 1H), 2.79 (t, J = 5.5 Hz, 2H), 2.59 (t, J = 5.5 Hz, 2H), 1.71−1.70 (m, 4H). 13C NMR (125 MHz, DMSO-d6) δ 161.4, 153.4, 153.3, 138.8, 135.9, 134.4, 132.3, 128.6, 126.3, 125.3, 123.6, 122.6, 117.1, 114.3, 83.2, 29.0, 24.0, 22.3, 22.2. MS (ESI): m/z = 292.3 [M + H]+. HRMS-ESI: calcd for C19H17NNaO2 [M + Na]+: 314.1151; found: 314.1160. 6-Methyl-4-(phenylamino)-2H-chromen-2-one (1o). Yellow solid, yield: 198 mg, 79%, m.p.306.2−307.8 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.08 (s, 1H), 7.51−7.47 (m, 3H), 7.39 (d, J = 7.5 Hz, 2H), 7.31−7.27 (m, 2H), 5.31 (s, 1H), 2.42 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.7, 152.4, 151.5, 138.3, 133.1, 132.9, 129.5, 125.9, 124.9, 122.5, 116.8, 114.2, 84.4, 20.5. MS (ESI): m/z = 252.3 [M + H]+. HRMS-ESI: calcd for C16H13NNaO2 [M + Na]+: 274.0838; found: 274.0847. 6-Methoxy-4-(phenylamino)-2H-chromen-2-one (1p). Yellow solid, yield: 190 mg, 71%, mp 265.2−266.9 °C (lit.23 269−270 °C). 1 H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 7.79 (d, J = 3.0 Hz, 1H), 7.52−7.49 (m, 2H), 7.39−7.37 (m, 2H), 7.33−7.30 (m, 2H), 7.27−7.24 (m, 1H), 5.30 (s, 1H), 3.87 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.7, 155.3, 152.4, 147.7, 138.2, 129.6, 126.1, 125.2, 119.9, 118.2, 114.8, 105.6, 84.6, 56.0. MS (ESI): m/z = 268.2 [M + H]+. HRMS-ESI: calcd for C16H13NNaO3 [M + Na]+: 290.0788; found: 290.0799. 6-Chloro-4-(phenylamino)-2H-chromen-2-one (1q). Yellow solid, yield: 217 mg, 80%, mp 300.1−300.7 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.40 (d, J = 2.5 Hz, 1H), 7.72(dd, J = 9.0, 2.5 Hz, 1H), 7.52−7.49 (m, 2H), 7.44 (d, J = 9.0 Hz, 1H), 7.39−7.37 (m, 2H), 7.32−7.29 (m, 1H), 5.36 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 161.0, 152.1, 151.5, 138.0, 132.1, 129.6, 127.9, 126.1, 124.9, 122.5, 119.1, 116.0, 84.9. MS (ESI): m/z = 272.2 [M + H]+. HRMS-ESI: calcd for C15H11NClO2 [M + H]+: 272.0473; found: 272.0485. 6-Methyl-4-(p-tolylamino)-2H-chromen-2-one (1r). Yellow solid, yield: 186 mg, 70%, mp 285.9−287.5 °C. 1H NMR (500 MHz,

DMSO-d6) δ 9.21 (s, 1H), 8.07 (s, 1H), 7.48 (dd, J = 8.0, 1.5 Hz, 1H), 7.30−7.24 (m, 5H), 5.22 (s, 1H), 2.42 (s, 3H), 2.35 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.7, 152.6, 151.5, 135.6, 135.3, 133.1, 132.8, 130.0, 125.1, 122.5, 116.8, 114.1, 84.0, 20.6, 20.5. MS (ESI): m/ z = 266.3 [M + H]+. HRMS-ESI: calcd for C17H15NNaO2 [M + Na]+: 288.0995; found: 288.0995. 4-((4-Chlorophenyl)amino)-6-methyl-2H-chromen-2-one (1s). Yellow solid, yield: 211 mg, 74%, mp 280.7−281.4 °C. 1H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.04 (s, 1H), 7.54 (d, J = 9.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 9.6 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 5.36 (s, 1H), 2.42 (s, 3H). 13C NMR (150 MHz, DMSO-d6) δ 162.0, 152.4, 151.9, 137.9, 133.6, 133.3, 130.0, 129.9, 126.8, 123.0, 117.3, 114.6, 85.6, 21.0. MS (ESI): m/z = 286.3 [M + H]+. HRMS-ESI: calcd for C16H12ClNNaO2 [M + Na]+: 308.0449; found: 308.0454. 6-Chloro-4-(p-tolylamino)-2H-chromen-2-one (1t). Yellow solid, yield: 200 mg, 70%, mp 300.7−301.1 °C. 1H NMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 7.70 (dd, J = 9.0, 2.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.31−7.24 (m, 4H), 5.27 (s, 1H), 2.35 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 161.0, 152.1, 151.7, 135.5, 135.3, 132.0, 130.1, 127.9, 125.0, 122.4, 119.0, 116.0, 84.5, 20.6. MS (ESI): m/z = 286.3 [M + H]+. HRMS-ESI: calcd for C16H12ClNNaO2 [M + Na]+: 308.0449; found: 308.0454. Typical Procedure for the Preparation of 9-Bromo-6Hchromeno[4,3-b]quinolin-6-one (2a). A mixture of Cu(OAc)2·H2O (15 mol %, 0.03 mmol, 7 mg), TBPB (3 equiv, 0.6 mmol, 116 mg), KOAc (1 equiv, 0.2 mmol, 20 mg), and DMF (3.5 mL) in a 10 mL flask was heated at 150 °C under oxygen atmosphere for 12 h. Then 4((4-bromophenyl)amino)-2H-chromen-2-one 1a (0.2 mmol, 63 mg) and NaHSO3 (1.2 equiv, 0.24 mmol, 25 mg) was added to the flask and heated at 150 °C under oxygen atmosphere for 24 h. The reaction mixture was cooled to room temperature, and then the solvent was removed under vacuum. The crude product was purified by column chromatography on silica gel (pure CH2Cl2) to yield 2a (52 mg, 80%) as a yellow solid. Isolated yield: 52 mg, 80%, mp 230.0−231.0 °C. 1H NMR (500 MHz, CDCl3) δ 9.10 (s, 1H), 8.74 (d, J = 7.5 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 9.0 Hz, 1H), 7.97−7.95 (m, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.45−7.38 (m, 2H). 13C NMR (125 MHz, CDCl3) δ 160.9, 152.7, 149.9, 149.5, 140.0, 136.8, 132.7, 131.1, 131.1, 128.2, 125.3, 125.1, 121.5, 119.3, 117.5, 116.4. MS (ESI): m/z = 326.1 [M + H]+. HRMS-ESI: calcd for C16H8BrNNaO2 [M + Na]+: 347.9631; found: 347.9616. 6H-Chromeno[4,3-b]quinolin-6-one (2b). Yellow solid. Isolated yield: 36 mg, 73%, mp 221.9−223.1 °C (lit.11 227−228 °C). 1H NMR (500 MHz, CDCl3) δ 9.22 (s, 1H), 8.79 (dd, J = 8.0, 1.5 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.02 (d, J = 9.0 Hz, 1H), 7.94−7.91 (m, 1H), 7.66−7.63 (m, 1H), 7.61−7.58 (m, 1H), 7.45−7.42 (m, 1H), 7.40 (dd, J = 8.5, 1.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 161.4, 152.7, 151.1, 149.6, 141.1, 133.4, 132.4, 129.6, 129.5, 127.4,127.4, 125.3, 125.0, 119.6, 118.4, 115.8. MS (ESI): m/z = 248.3 [M + H]+. [M + H]+. HRMS-ESI: calcd for C16H9NNaO2 [M + Na]+: 270.0525; found: 270.0524. 9-Methyl-6H-chromeno[4,3-b]quinolin-6-one (2c). Yellow solid. Isolated yield: 42 mg, 81%, mp 234.3−235.1 °C (lit.11 201−203 °C). 1 H NMR (500 MHz, CDCl3) δ 9.15 (s, 1H), 8.84 (dd, J = 8.0, 1.5 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 7.78−7.76 (m, 2H), 7.62−7.59 (m, 1H), 7.47−7.43 (m, 1H), 7.42 (dd, J = 8.0, 1.0 Hz, 1H), 2.61 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ 161.4, 152.6, 149.6, 148.8, 140.4, 137.8, 136.1, 132.3, 129.0, 128.0, 127.4, 125.3, 125.0, 119.6, 117.4, 115.8, 21.7. MS (ESI): m/z = 262.4 [M + H]+. HRMS-ESI: calcd for C17H12NO2 [M + H]+: 262.0863; found: 262.0850. 9-Ethyl-6H-chromeno[4,3-b]quinolin-6-one (2d). Yellow solid. Isolated yield: 41 mg, 75%, mp 152.8−154.5 °C. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.71 (dd, J = 8.0, 1.6 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.75−7.70 (m, 2H), 7.56−7.52 (m, 1H), 7.40−7.36 (m, 1H), 7.35 (d, J = 8.0 Hz, 1H), 2.89 (q, J = 3.6 Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 160.6, 151.9, 149.2, 148.2, 143.2, 139.8, 134.4, 131.6, 128.8, 127.0, 126.1, 124.7, 124.4, 119.3, 117.0, 115.4, 29.2, 15.6. MS (ESI): m/z = 276.3 [M + H]+. HRMSESI: calcd for C18H13NNaO2 [M + Na]+: 298.0838; found: 298.0845. 9051

DOI: 10.1021/acs.joc.7b01515 J. Org. Chem. 2017, 82, 9047−9053

Article

The Journal of Organic Chemistry

(500 MHz, CDCl3) δ 9.05 (s, 1H), 8.81 (dd, J = 7.5, 1.5 Hz, 1H), 7.59−7.56 (m, 3H), 7.45−7.42 (m, 1H), 7.40 (dd, J = 8.0, 1.0 Hz, 1H), 2.90 (s, 3H), 2.55 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.7, 152.6, 148.9, 147.6, 140.1, 137.3, 137.3, 135.8, 131.8, 127.5, 125.8, 125.1, 124.8, 120.2, 117.3, 115.4, 21.7, 17.8. MS (ESI): m/z = 276.1 [M + H]+. HRMS-ESI: calcd for C18H14NO2 [M + H]+: 276.1019; found: 276.1029. 6H-Benzo[h]chromeno[4,3-b]quinolin-6-one (2m). Yellow solid. Isolated yield: 38 mg, 63%, mp 290.4−292.1 °C. 1H NMR (600 MHz, CDCl3) δ 9.54−9.52 (m, 1H), 9.14 (s, 1H), 8.98 (dd, J = 7.8, 1.2 Hz, 1H), 7.96 (dd, J = 6.0, 2.4 Hz, 1H), 7.88−7.86 (m, 1H), 7.83−7.80 (m, 3H), 7.64−7.61 (m, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.45 (d, J = 7.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 161.6, 152.8, 150.5, 148.9, 139.3, 135.2, 132.2, 130.9, 130.2, 129.0, 128.2, 127.6, 126.0, 125.8, 125.5, 125.2, 125.0, 120.0, 117.4, 115.8. MS (ESI): m/z = 298.1 [M + H]+. HRMS-ESI: calcd for C20H12NO2 [M + H]+: 298.0863; found: 298.0876. 10,11,12,13-Tetrahydro-6H-benzo[h]chromeno[4,3-b]quinolin-6one (2n). White solid. Isolated yield: 34 mg, 56%, mp 272.5−273.2 °C. 1H NMR (500 MHz, CDCl3) δ 9.02 (s, 1H), 8.76 (dd, J = 8.0, 1.5 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.57−7.54 (m, 1H), 7.42−7.39 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 3.43 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.01−1.92 (m, 4H). 13C NMR (125 MHz, CDCl3) δ 161.7, 152.6, 149.9, 148.2, 142.9, 140.4, 135.3, 131.9, 130.00, 126.00, 125.7, 125.2, 124.8, 120.2, 117.3, 114.5, 30.7, 24.7, 22.7. MS (ESI): m/z = 302.5 [M + H]+. HRMS-ESI: calcd for C20H15NNaO2 [M + Na]+: 324.0995; found: 324.1006. 2-Methyl-6H-chromeno[4,3-b]quinolin-6-one (2o). Yellow solid. Isolated yield: 36 mg, 70%, mp 225.0−226.3 °C, 1H NMR (500 MHz, CDCl3) δ 9.20 (s, 1H), 8.55 (d, J = 1.5 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.02(dd, J = 8.0, 1.0 Hz, 1H), 7.94−7.91 (m, 1H), 7.66−7.62 (m, 1H), 7.40 (dd, J = 8.5, 1.5 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 2.52 (s, 3H). 13C NMR (125 MHz, CDCl3) δ161.4, 151.0, 150.8, 149.7, 141.1, 134.7, 133.3, 130.9,129.4, 129.4, 127.3, 127.2, 124.9, 119.1, 117.1, 115.8, 21.0. MS (ESI): m/z = 262.4 [M + H]+. HRMS-ESI: calcd for C17H12NO2 [M + H]+: 262.0863; found: 262.0861. 2-Methoxy-6H-chromeno[4,3-b]quinolin-6-one (2p). Yellow solid. Isolated yield: 39 mg, 70%, mp 230.7−231.3 °C. 1H NMR (600 MHz, CDCl3) δ 9.22 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.93 (t, J = 7.2 Hz, 1H), 7.65 (t, J = 8.4 Hz, 1H), 7.31 (d, J = 9.0 Hz, 1H), 7.16 (dd, J = 9.0, 2.4 Hz, 1H), 4.00 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 161.4, 156.7, 150.8, 149.5, 147.1, 141.3, 133.5, 129.4 (d, J = 6.0 Hz), 127.5, 127.3, 120.7, 119.9, 118.6, 115.7, 106.8, 56.1. MS (ESI): m/z = 278.4 [M + H]+. HRMSESI: calcd for C17H12NO3 [M + H]+: 278.0812; found: 278.0823. 2-Chloro-6H-chromeno[4,3-b]quinolin-6-one (2q). White solid. Isolated yield: 42 mg, 74%, mp 268.7−269.1 °C (lit.24273 °C). 1H NMR (600 MHz, CDCl3) δ 9.26 (s, 1H), 8.79−8.78 (m, 1H), 8.29− 8.27 (m, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.99−7.96 (m, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.56 (dd, J = 9.0, 2.4 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H). 13 C NMR (150 MHz, CDCl3) δ 160.9, 151.1, 151.0, 148.5, 141.3, 133.7, 132.3, 130.7, 129.6, 129.5, 127.9, 127.5, 124.9, 120.9, 118.9, 115.6. MS (ESI): m/z = 282.2 [M + H]+. HRMS-ESI: calcd for C16H9ClNO2 [M + H]+: 282.0316; found: 282.0325. 2,9-Dimethyl-6H-chromeno[4,3-b]quinolin-6-one (2r). Yellow solid. Isolated yield: 40 mg, 72%, mp 210.0−211.9 °C. 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 8.54 (s, 1H), 8.13 (d, J = 9.0 Hz, 1H), 7.74−7.73 (m, 2H), 7.38 (dd, J = 8.5, 1.5 Hz, 1H), 7.27 (d, J = 3.5 Hz, 1H), 2.58 (s, 3H), 2.51 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.6, 150.6, 149.7, 148.9, 140.1, 137.5, 135.8, 134.6, 133.0, 129.1, 127.9, 127.3, 124.8, 119.3, 117.1, 115.7, 21.6, 21.0. MS (ESI): m/z = 276.3 [M + H]+. HRMS-ESI: calcd for C18H14NO2 [M + H]+: 276.1019; found: 276.1009. 9-Chloro-2-methyl-6H-chromeno[4,3-b]quinolin-6-one (2s). White solid. Isolated yield: 44 mg, 75%, mp 246.5−248.5 °C (lit.12 252−253 °C). 1H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 8.0, 2.5 Hz, 1H), 7.41 (dd, J = 8.0, 2.0 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 2.52 (s, 3H). 13C NMR (125 MHz, DMSO) δ 161.0, 150.8, 149.9, 149.3, 140.0, 134.9, 134.2, 133.6, 133.2,131.0,127.7,127.6,

9-Methoxy-6H-chromeno[4,3-b]quinolin-6-one (2e). Yellow solid. Isolated yield: 36 mg, 66%, mp 233.5−235.0 °C (lit.11 236−237 °C). 1 H NMR (500 MHz, CDCl3) δ 9.09 (s, 1H), 8.77 (dd, J = 7.5, 1.0 Hz, 1H), 8.16 (d, J = 9.5 Hz, 1H), 7.59−7.55 (m, 2H), 7.44−7.38 (m, 2H), 7.22 (d, J = 2.8 Hz, 1H), 3.99 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.6, 158.5, 152.4, 147.6, 147.5, 139.0, 131.8, 131.0, 128.6, 127.2, 124.9, 124.9, 119.8, 117.3, 115.9, 105.6, 55.8. MS (ESI): m/z = 278.2 [M + H]+. HRMS-ESI: calcd for C17H12NO3 [M + H]+: 278.0812; found: 278.0809. 9-Ethoxy-6H-chromeno[4,3-b]quinolin-6-one (2f). Yellow solid. Isolated yield: 43 mg, 74%, mp 228.0−228.7 °C (lit.11 229−230 °C). 1 H NMR (600 MHz, CDCl3) δ 9.08 (s, 1H), 8.79 (d, J = 7.8 Hz, 1H), 8.19 (d, J = 9.6 Hz, 1H), 7.59−7.56 (m, 2H), 7.45 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 3.0 Hz, 1H), 4.22 (q, J = 6.6 Hz, 2H), 1.54 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 161.5, 157.8, 152.3, 147.3, 147.3, 139.1, 131.9, 130.8, 128.6, 127.5, 125.0, 124.9, 119.6, 117.3, 115.9, 106.2, 64.2, 14.7. MS (ESI): m/z = 292.2 [M + H]+. HRMS-ESI: calcd for C18H14NO3 [M + H]+: 292.0968; found: 292.0959. 9-Chloro-6H-chromeno[4,3-b]quinolin-6-one (2g). Yellow solid. Isolated yield: 41 mg, 73%, mp 245.7−246.4 °C (lit.11 246−247 °C). 1 H NMR (500 MHz, CDCl3) δ 9.12 (s, 1H), 8.76 (d, J = 7.5 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 7.85 (dd, J = 9.0, 2.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.40 (dd, J = 8.5, 1.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) δ 161.0, 152.7, 149.9, 149.5, 140.0, 134.3, 133.4, 132.7, 131.2, 127.7, 127.7, 125.3, 125.1, 119.4, 117.5, 116.5. MS (ESI): m/z = 282.3 [M + H]+. HRMSESI: calcd for C16H8ClNNaO2 [M + Na]+: 304.0136; found: 304.0146. 9-Fluoro-6H-chromeno[4,3-b]quinolin-6-ones (2h). Yellow solid. Isolated yield: 32 mg, 60%, mp 242.3−243.0 °C. 1H NMR (600 MHz, CDCl3) δ 9.19 (s, 1H), 8.79 (dd, J = 7.8, 1.2 Hz, 1H), 8.30−8.27 (m, 1H), 7.73−7.70 (m, 1H), 7.65−7.60 (m, 2H), 7.46−7.44 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 161.1, 160.8 (JC−F = 251.9 Hz), 152.6, 149.1, 148.2, 140.4, 140.4, 132.5, 132.1 (JC−F = 9.0 Hz), 127.8 (JC−F = 10.4 Hz), 125.1 (JC−F = 8.1 Hz), 124.1 (JC−F = 26.3 Hz), 119.3, 117.5, 116.4, 112.0 (JC−F = 21.9 Hz). MS (ESI): m/ z = 266.2 [M + H]+. HRMS-ESI: calcd for C16H9FNO2 [M + H]+: 266.0612; found: 266.0611. Ethyl 6-Oxo-6H-chromeno[4,3-b]quinoline-9-carboxylate (2i). White solid. Isolated yield: 45 mg, 71%, mp 263.4−263.9 °C. 1H NMR (600 MHz, CDCl3) δ 9.36 (s, 1H), 8.85 (d, J = 7.2 Hz, 1H), 8.78 (d, J = 1.2 Hz, 1H), 8.52−8.50 (m, 1H), 8.33 (dd, J = 8.4, 1.2 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.52 (q, J = 7.2 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 165.5, 160.8, 153.0, 152.5, 151.4, 142.8, 133.2, 132.8, 132.3, 129.7, 129.3, 126.5, 125.7, 125.2, 119.2, 117.6, 116.5, 61.8, 14.4. MS (ESI): m/z = 320.2 [M + H]+. HRMS-ESI: calcd for C19H13NaNO4 [M + Na]+: 342.0737; found: 342.0735. 11-Methyl-6H-chromeno[4,3-b]quinolin-6-one (2j). Yellow solid. Isolated yield: 38 mg, 73%, mp 209.6−211.7 °C(lit.11 201−203 °C). 1 H NMR (500 MHz, CDCl3) δ 9.14 (s, 1H), 8.80 (dd, J = 7.5, 1.5 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.0 Hz, 1H), 7.60−7.57 (m, 1H), 7.53 (dd, J = 8.0, 7.0 Hz, 1H), 7.45−7.42 (m, 1H), 7.39 (dd, J = 7.5, 1.0 Hz, 1H), 2.92 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.6, 152.7, 150.1, 148.4, 141.1, 137.8, 133.2, 132.1, 127.5, 127.4, 127.2, 125.2, 124.9, 120.1, 117.4, 115.4, 17.9. MS (ESI): m/z = 262.4 [M + H]+. HRMS-ESI: calcd for C17H12NO2 [M + H]+: 262.0863; found: 262.0870. 11-Methoxy-6H-chromeno[4,3-b]quinolin-6-one (2k). Yellow solid. Isolated yield: 44 mg, 80%, mp 219.2−220.2 °C (lit.11 236− 237 °C). 1H NMR (500 MHz, CDCl3) δ 9.11 (s, 1H), 8.79 (dd, J = 7.5, 1.5 Hz, 1H), 7.60−7.55 (m, 1H), 7.54−7.50 (m, 2H), 7.43−7.39 (m, 1H), 7.37 (dd, J = 8.5, 0.5 Hz, 1H), 7.20 (dd, J = 6.5, 2.0 Hz, 1H), 4.13 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 161.2, 155.2, 152.5, 148.4, 143.0, 140.7, 132.2, 128.3, 127.6, 125.5, 124.8, 120.9, 119.6, 117.2, 116.0, 111.1, 56.3. MS (ESI): m/z = 278.2 [M + H]+. HRMSESI: calcd for C17H12NO3 [M + H]+: 278.0812; found: 278.0825. 9,11-Dimethyl-6H-chromeno[4,3-b]quinolin-6-one (2l). Yellow solid. Isolated yield: 38 mg, 70%, mp 219.8−220.5 °C. 1H NMR 9052

DOI: 10.1021/acs.joc.7b01515 J. Org. Chem. 2017, 82, 9047−9053

Article

The Journal of Organic Chemistry 124.9, 118.8, 117.2, 116.5, 21.0. MS (ESI): m/z = 296.4 [M + H]+. HRMS-ESI: calcd for C17H11ClNO2 [M + H]+: 296.0473; found: 296.0477. 2-Chloro-9-methyl-6H-chromeno[4,3-b]quinolin-6-one (2t). White solid. Isolated yield: 44 mg, 75%, mp 274.8−276.2 °C (lit.24 280 °C). 1H NMR (600 MHz, CDCl3) δ 9.15 (s, 1H), 8.77 (d, J = 3.0 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 7.80 (d, J = 6.6 Hz, 2H), 7.54 (dd, J = 8.4, 2.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 2.62 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 161.0, 150.9, 149.7, 147.7, 140.4, 138.2, 136.3, 132.0, 130.6, 129.2, 128.0, 127.6, 124.8, 121.0, 118.9, 115.5, 21.7. MS (ESI): m/z = 296.4 [M + H]+. HRMS-ESI: calcd for C17H11ClNO2 [M + H]+: 296.0473; found: 296.0479.

■

Motamedi, M.; Jones, T. K.; Marschke, K. B.; Mais, D. E.; Risek, B.; Schrader, W. T. J. Med. Chem. 2003, 46, 4104−4112. (11) Tabakovic, K.; Tabakovic, I.; Ajdini, N.; Leci, O. Synthesis 1987, 3, 308−310. (12) Wu, J.; Wang, X. Org. Biomol. Chem. 2006, 4, 1348−1351. (13) Rajawinslin, R. R.; Gawande, S. D.; Kavala, Y.; Huang, Y.-H.; Kuo, C.-W.; Kuo, T.-S.; Chen, M.-L.; He, C.-H.; Yao, C.-F. RSC Adv. 2014, 4, 37806−37811. (14) (a) Johansson, M. J.; Andersson, K. H. O.; Kann, N. J. Org. Chem. 2008, 73, 4458−4463. (b) Suchy, M.; Elmehriki, A. A. H.; Hudson, R. H. E. Org. Lett. 2011, 13, 3952−3955. (c) Liu, L.; ZhangNegrerie, D.; Du, F.; Zhao, K. Org. Lett. 2014, 16, 436−439. (15) (a) Wang, J.; Hou, J.-T.; Wen, J.; Zhang, J.; Yu, X.-Q. Chem. Commun. 2011, 47, 3652−3654. (b) Chen, W.-X.; Shao, L.-X. J. Org. Chem. 2012, 77, 9236−9239. (c) Huang, X.; Wang, J.; Ni, Z.; Wang, S.; Pan, Y. Chem. Commun. 2014, 50, 4582−4584. (16) (a) Kim, J.; Chang, S. J. Am. Chem. Soc. 2010, 132, 10272− 10274. (b) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374− 12377. (c) Kim, J.; Kim, H.; Chang, S. Org. Lett. 2012, 14, 3924−3927. (17) Borah, A.; Goswami, L.; Neog, K.; Gogoi, P. J. Org. Chem. 2015, 80, 4722−4728. (18) Li, Y.; Xue, D.; Lu, W.; Wang, C.; Liu, Z.-T.; Xiao, J. Org. Lett. 2014, 16, 66−69. (19) Liu, J.; Yi, H.; Zhang, X.; Liu, C.; Liu, R.; Zhang, G.; Lei, A. Chem. Commun. 2014, 50, 7636−7638. (20) Rao, D. N.; Rasheed, S.; Das, P. Org. Lett. 2016, 18, 3142−3145. (21) (a) Zhao, M.-N.; Hui, R.-R.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.H. Org. Lett. 2014, 16, 3082−3085. (b) Liu, W.; Tan, H.; Chen, C.; Pan, Y. Adv. Synth. Catal. 2017, 359, 1594−1598, DOI: 10.1002/ adsc.201601225. (22) (a) Pu, F.; Li, Y.; Song, Y.; Xiao, J.; Liu, Z.; Wang, C.; Liu, Z.; Chen, J.; Lu, J. Adv. Synth. Catal. 2016, 358, 539−542. (b) Mondal, S.; Samanta, S.; Santra, S.; Bagdi, A. K.; Hajra, A. Adv. Synth. Catal. 2016, 358, 3633−3641. (23) Di Braccio, M.; Grossi, G.; Roma, G.; Marzano, C.; Baccichetti, F.; Simonato, M.; Bordin, F. Farmaco 2003, 58, 1083−1097. (24) Heber, D. Arch. Pharm. 1987, 320, 595−599.

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01515. Copies of 1H and 13C NMR spectra of all starting materials and products (PDF)

■

AUTHOR INFORMATION

Corresponding Authors

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

Yuanyuan Xie: 0000-0001-8482-9948 Weike Su: 0000-0001-5072-1509 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (nos. 21506190, 21576239, 21506191) and Natural Science Foundation of Zhejiang Province (no. LQ16B060005) for financial support.

■

REFERENCES

(1) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166−187. (2) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles, 2nd ed.; Wiley-VCH: Weinheim, 2003; pp 316−336. (3) Kharb, R.; Kaur, H. Int. Res. J. Pharm. 2013, 4, 63−69. (4) Kaur, K.; Jain, M.; Reddy, R. P.; Jain, R. Eur. J. Med. Chem. 2010, 45, 3245−3264. (5) Bureau, Y.; Handa, M.; Zhu, Y.; Laliberte, F.; Moore, C. S.; Liu, S.; Huang, A.; MacDonald, D.; Xu, D. G.; Robertson, G. S. Neuropharmacology 2006, 51, 974−985. (6) (a) Kerrigan, J. E.; Pilch, D. S. Biochemistry 2001, 40, 9792−9798. (b) Thomas, C. J.; Rahier, N. J.; Hecht, S. M. Bioorg. Med. Chem. 2004, 12, 1585−1604. (c) Solomon, V. R.; Lee, H. Curr. Med. Chem. 2011, 18, 1488−1508. (7) Sashidhara, K. V.; Palnati, G. R.; Singh, L. R.; Upadhyay, A.; Avula, S. R.; Kumar, A.; Kant, R. Green Chem. 2015, 17, 3766−3770. (8) (a) Muruganantham, N.; Sivakumar, R.; Anbalagan, N.; Gunasekaran, V.; Leonard, J. T. Biol. Pharm. Bull. 2004, 27, 1683− 1687. (b) Mulakayala, N.; Rambabu, D.; Raja, M. R.; Chaitanya, M.; Kumar, C. K.; Kalle, A. M.; Krishna, G. R.; Reddy, C. M.; Rao, M. V.; Pal, M. Bioorg. Med. Chem. 2012, 20, 759−768. (c) Goswami, L.; Gogoi, S.; Gogoi, J.; Boruah, R. K.; Boruah, R. C.; Gogoi, P. ACS Comb. Sci. 2016, 18, 253−261. (9) Huang, W.; Lin, W.; Guan, X. Tetrahedron Lett. 2014, 55, 116− 119. (10) (a) Vu, A. T.; Campbell, A. N.; Harris, H. N.; Unwalla, R. J.; Manas, E. S.; Mewshaw, R. E. Bioorg. Med. Chem. Lett. 2007, 17, 4053−4056. (b) Zhi, L.; Tegley, C. M.; Pio, B.; Edwards, J. P.; 9053

DOI: 10.1021/acs.joc.7b01515 J. Org. Chem. 2017, 82, 9047−9053