HETEROCYCLES

Short Paper | Special issue | Vol. 90, No. 2, 2015, pp. 1332-1342
Received, 15th July, 2014, Accepted, 4th August, 2014, Published online, 19th August, 2014.
DOI: 10.3987/COM-14-S(K)84

■ Palladium-Mediated Intramolecular Biaryl Coupling Reaction: Convenient Preparation of Furoquinolinone Derivatives

Hitoshi Abe,* Mayu Kamimura, Yoshinori Komatsu, and Yoshikazu Horino

Department of Environmental Applied Chemistry, Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

Furo[2,3-c] or furo[3,2-c]quinolinone derivatives were prepared via the intramolecular biaryl coupling reaction of 2-furoylanilides or 3-furoylanilides using a palladium catalyst.

Furoquinoline derivatives are widely distributed in nature, which often exhibit interesting biological properties such as antifungal, antibacterial, antiviral, and antimicrobial activities.1 Therefore, the development of a synthetic method for furoquinolines is an important subject whereas there have been only limited methods known in the literature.2,3
In this context, an intramolecular biaryl coupling reaction using a palladium catalyst4 must be an efficient technique for the preparation of the furo[2,3-c] or furo[3,2-c]quinolinone. Although a few examples have been reported for the transformation into these compounds by a palladium-catalyzed reaction,3 a systematic investigation has never been reported. In this short report, we demonstrate the palladium-mediated biaryl coupling reaction of several types of furoylanilides for the preparation of furoquinolinone derivatives.
We first prepared six furoylanilides (1a-1c and 2a-2c) as the precursor of the intramolecular coupling reaction. These compounds were easily derived from 2-furancarboxylic acid by the conventional amidation (see experimental section). In Table 1, the coupling reaction was carried out under the conditions of using Pd(OAc)2, Ph3P, NaOAc, and DMA. Among the employed substrates 1a-1c, which furnish an iodo atom on the side of the anilide moiety, the reaction of the N-unsubstituted 1a did not afford the desired coupling product 3a (entry 1). On the other hand, N-methyl anilide5 1b and N-MOM anilide6 1c were transformed into the corresponding furoquinolinones 3b and 3c, respectively (entries 2 and 3).
The substrates 2a-2c, which have the iodo atom on the furan ring, were also examined under the same conditions. Similar to the results of entries 1-3, the unsubstituted compound 2a did not give the coupling product 3a (entry 4),7 whereas the N-methyl and N-MOM anilides, 2b and 2c, were converted into the cyclized products 3b and 3c, respectively (entries 5 and 6).

Next, Table 2 shows the reaction of the other types of substrates, 3-furoylanilides (4a-4c and 5a-5c). Similar to the results of Table 1, the unsubstituted materials 4a and 5a did not produce furoquinolinone 6a (entries 1 and 4). On the contrary, the N-methylanilides 4b and 5b, and N-MOM anilides 4c and 5c produced the coupling compounds 6b and 6c, respectively (entries 2, 3, 5, and 6).
All attempts to obtain the NH products 3a and 6a directly from the unsubstituted NH anilides 1a, 2a, 4a and 5a were unsuccessful. However, when 3c and 6c were treated with aqueous acid, the MOM group was smoothly eliminated to afford 3a and 6a, respectively (Scheme).
In conclusion, we investigated the Pd-mediated intramolecular coupling reaction of several furoylanilide derivatives. The formation of N-substituted furoquinolinones was successful although the NH products were not formed by this procedure. Alternatively, the N-MOM derivatives could be transformed into the NH furoquinolinones by treatment with aqueous acid.

EXPERIMENTAL
General Information
Melting points were measured using a Yanagimoto MP-500D micro melting point hot-plate apparatus and are uncorrected. The IR spectra were recorded using a SHIMADZU FTIR-8400 spectrophotometer. The NMR spectra were obtained using a JEOL α-400 (400 MHz), JNM-ECX500, or JNM-ECP600 instrument. The chemical shifts are given in δ ppm with TMS as the internal standard. The elemental analyses were performed using a Thermo Scientific FlashEA1112 analyzer. The MS were obtained using a JMS-AX505HAD. Silica gel column chromatography was carried out using a Wakogel® C-200.

Preparation of substrates 1a-1c, 2a-2c, 4a-4c, and 5a-5c
N-(2-Iodophenyl)-2-furamide (1a)8
A mixture of 2-furancarbonyl chloride (10.4 g, 79.7 mmol), 2-iodoaniline (17.5 g, 79.9 mmol), and CH2Cl2 (200 mL) was stirred for 2 h at rt. After extractive work-up with CH2Cl2, the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was recrystallized from MeOH to give 1a (16.9 g, 68%). Yellow ocher solid, mp 80.9-83.7 ˚C (MeOH). 1H-NMR (400 MHz, CDCl3) δ: 6.59 (1H, dd, J = 2.0, 3.2 Hz, 4-H), 6.88 (1H, dt, J = 1.2, 7.6 Hz, 4’-H or 5’-H), 7.28 (1H, d, J = 3.2 Hz, 3-H), 7.39 (1H, t, J = 7.6 Hz, 4’-H or 5’-H), 7.58 (1H, d, J = 1.2 Hz, 5-H), 7.82 (1H, dd, J = 1.2, 8.0 Hz, 3’-H or 6’-H), 8.41 (1H, d, J = 6.8 Hz, 3’-H or 6’-H), 8.51 (1H, s, NH). 13C-NMR (100 MHz, CDCl3) δ: 89.9, 112.8, 115.8, 121.7, 126.1, 129.4, 138.0, 139.0, 144.8, 147.7, 156.1. IR (KBr): νmax 577, 753, 936, 1010, 1163, 1306, 1430, 1531, 1583, 1594, 3113, 3115, 3367 cm−1. Anal. Calcd for C11H8INO2: C, 42.20; H, 2.58; N, 4.47. Found: C, 41.99; H, 2.72; N, 4.43.
N-(2-Iodophenyl)-N-methyl-2-furamide (1b)
To a suspension of NaH (60%, 7.53 mg, 0.188 mmol) and DMF (1 mL), a solution of 1a (52.1 mg, 0.166 mmol) in DMF (1 mL) was added, and the mixture was stirred for 1 h. MeI (0.010 mL, 0.161 mmol) was added and the mixture was stirred for 2 h at rt. After quenching the reaction with water and extractive work-up with AcOEt, the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was subjected to silica gel column chromatography with AcOEt to produce 1b (44.6 mg, 82%). Colorless solid, mp 148.3-149.7 ˚C (AcOEt). 1H-NMR (400 MHz, CDCl3) δ: 3.35 (3H, s, NMe), 5.81 (1H, s, 4-H), 6.20 (1H, s, 3-H), 7.11 (1H, ddd, J = 1.6, 7.2, 7.6 Hz, 4’-H or 5’-H), 7.29 (2H, m, 3’-H or 6’-H, 5-H), 7.42 (1H, ddd, J = 1.6, 7.6, 7.6 Hz, 4’-H or 5’-H), 7.93 (1H, dd, J = 1.6, 7.6 Hz, 3’-H or 6’-H). 13C-NMR (100 MHz, CDCl3) δ: 37.1, 99.4, 111.0, 115.9, 129.2, 129.8, 129.9, 140.0, 144.4, 146.0, 146.8, 158.7. IR (KBr): νmax 580, 724, 747, 774, 886, 1007, 1106, 1239, 1304, 1391, 1415, 1472, 1558, 1634, 2860, 2925, 3126 cm−1 Anal. Calcd for C12H10INO2: C, 44.06; H, 3.08; N, 4.28. Found: C, 44.05; H, 3.31; N, 4.08.
N-(2-Iodophenyl)-N-methoxymethyl-2-furamide (1c)
To a suspension of NaH (60%, 19.6 mg, 0.49 mmol) and DMF (1.5 mL), a solution of 1a (50.4 mg, 0.161 mmol) in DMF (1 mL) was added, and the mixture was stirred for 30 min. MOMCl (0.018 mL, 0.24 mmol) was added and the mixture was stirred for 1.5 h at rt. After quenching the reaction with water and extractive work-up with AcOEt, the organic layer was washed with brine, dried over MgSO4, and evaporated. The resulting residue was subjected to silica gel column chromatography with AcOEt/hexane (1/4) to produce 1c (31.1 mg, 54%). Colorless solid, mp 92.5-94.5 ˚C (AcOEt). 1H-NMR (400 MHz, CDCl3) δ: 3.53 (3H, s, OMe), 4.57 (1H, d, J = 10 Hz, 4-H), 5.77 (2H, d, J = 10 Hz, CH2), 6.23 (1H, s, 3-H), 7.14 (1H, ddd, J = 1.6, 7.6, 7.6 Hz, 4’-H or 5’-H), 7.35 (1H, dd, J = 1.6, 7.6 Hz, 3’-H or 6’-H), 7.38 (1H, s, 5-H), 7.44 (1H, dt, J = 1.6, 7.2 Hz, 4’-H or 5’-H), 7.94 (1H, dd, J = 1.6, 7.6 Hz, 3’-H or 6’-H). 13C-NMR (100 MHz, CDCl3) δ: 57.4, 79.3, 100.6, 111.5, 117.2, 129.6, 130.3, 131.2, 140.1, 143.6, 145.3, 146.6, 159.6. IR (KBr): νmax 596, 652, 729, 785, 910, 997, 1038, 1078, 1099, 1190, 1304, 1400, 1466, 1556, 1649, 2939, 3117 cm−1. Anal. Calcd for C13H12INO3: C, 43.72; H, 3.39; N, 3.92. Found: C, 43.81; H, 3.59; N, 3.89.
3-Iodofuran-2-carboxylic acid9
A solution of furan-2-carboxylic acid (5.01 g, 44.7 mmol) in THF (90 mL) was dropwise added at -78 oC to a solution of LDA (96.3 mmol) in THF (200 mL). After 1 h, TMSCl (6.80 mL, 53.6 mmol) was dropwise added, and then the mixture was allowed to warm to rt. The reaction mixture was stirred for 2.5 h at the same temperature, and quenched with a 5N HCl aqueous solution (10 mL). After extractive work-up with Et2O, the organic layer was washed with brine, dried over MgSO4, and evaporated to give a solid material which was recrystallized from CHCl3. The colorless solid of 5-trimethylsilyl-furan-2-carboxylic acid (7.61 g, 92%) was obtained.
To a solution of the above compound (7.59 g, 41.2 mmol) in THF, nBuLi (61.0 mL, 97.0 mmol, 1.59 M in hexane) was dropwise added at -78 oC. After 1 h, a solution of I2 (15.7 g, 61.9 mmol) in THF (160 mL) was dropwise added to the mixture at the same temperature, then the mixture was allowed to warm to rt and left to stand for 7 h. The reaction was quenched with a sat. NH4Cl aqueous solution. After extractive work-up with Et2O, the organic layer was successively washed with a Na2S2O3 aqueous solution and brine, dried over MgSO4, and evaporated. The resulting residue was subjected to silica gel column chromatography with Et2O/AcOH/hexane (50:5:400) to give a brown solid of 2-iodo-3-trimethylsilyl-furan-2-carboxylic acid (8.88 g, 69%).
A mixture of the above compound (8.83 g, 28.5 mmol), THF (120 mL), and TBAF (1M in THF, 62.5 mL, 62.5 mmol) was heated for 10 h under reflux. After cooling, a 1N H2SO4 aqueous solution was added to the mixture. The mixture was extracted with ether, and the organic layer was successively washed with Na2S2O3 aqueous solution and brine, dried over MgSO4, and evaporated. The crude product was subjected to silica gel column chromatography with CHCl3/AcOH/hexane (50:5:450) to give a solid which was further recrystallized from CHCl3. The title compound (4.91 g, 72%) was obtained as colorless crystallines, mp 161.3-163.3 ˚C (CHCl3). 1H-NMR (400 MHz, CDCl3) δ: 6.75 (1H, d, J = 2.0 Hz, 4-H), 7.57 (1H, d, J = 1.6 Hz, 5-H). 1H-NMR (400 MHz, DMSO-d6) δ: 6.87 (1H, d, J = 1.6 Hz, 4-H), 7.89 (1H, d, J = 2.0 Hz, 5-H), 13.3 (1H, s, -COOH). 13C-NMR (100 MHz, DMSO-d6) δ: 75.8, 121.4, 144.0, 147.8, 159.1. IR (KBr): νmax 762, 789, 887, 976, 1072, 1202, 1288, 1481, 1560, 1682 cm−1. Anal. Calcd for C5H3IO3: C, 25.23; H, 1.27. Found: C, 25.31; H, 1.05.
N-Phenyl-2-(3-iodo)furamide (2a)
A mixture of 3-iodofuran-2-carboxylic acid (100 mg, 0.420 mmol), aniline (0.0480 mL, 0.526 mmol), EDC (124 mg, 0.646 mmol), DMAP (28.2 mg, 0.231 mmol), and CH2Cl2 (4 mL) was stirred for 1 h at rt. The mixture was successively washed with a 10% HCl, a 10% NaOH aqueous solution, and brine, then dried over MgSO4, and evaporated. The resulting residue was subjected to silica gel column chromatography with CH2Cl2/ AcOEt /hexane (1/1/16) to give 2a (122 mg, 93%), a colorless solid, mp 119.9-121.6 ˚C (AcOEt). 1H-NMR (400 MHz, CDCl3) δ: 6.73 (1H, d, J = 2.0 Hz, 4-H), 7.15 (1H, t, J = 7.2 Hz, 4’-H), 7.36 (2H, t, J = 8.4, 3’, 5’-H), 7.48 (1H, d, J = 1.6 Hz, 5-H), 7.66 (2H, dd, J = 0.8, 8.4 Hz, 2’, 6’-H), 8.12 (1H, s, NH). 13C-NMR (100 MHz, CDCl3) δ: 70.5, 120.0, 122.0, 124.8, 129.2, 137.3, 145.0, 155.7. IR (KBr): νmax 505, 691, 745, 1061, 1184, 1321, 1483, 1572, 1601, 1653, 2332, 3123, 3244 cm−1. Anal. Calcd for C11H8INO2: C, 42.20; H, 2.58; N, 4.47. Found: C, 42.33; H, 2.26; N, 4.37.

N-Methyl-N-phenyl-2-(3-iodo)furamide (2b)
By the same procedure used for the preparation of 1b, 2b (44.6 mg, 82%) was obtained from 2a (52.1 mg, 0.166 mmol), a colorless solid, mp 148.3-149.7 ˚C (AcOEt). 1H-NMR (400 MHz, CDCl3) δ: 3.35 (3H, s, NMe), 5.81 (1H, s, 4-H), 6.20 (1H, s, 3-H), 7.11 (1H, ddd, J = 1.6, 7.2, 7.6 Hz, 4’-H or 5’-H), 7.29 (2H, m, 3’-H or 6’-H, 5-H), 7.42 (1H, ddd, J = 1.6, 7.6, 7.6 Hz, 4’-H or 5’-H), 7.93 (1H, dd, J = 1.6, 7.6 Hz, 3’-H or 6’-H). 13C-NMR (100 MHz, CDCl3) δ: 37.1, 99.4, 111.0, 115.9, 129.2, 129.8, 129.9, 140.0, 144.4, 146.0, 146.8, 158.7. IR (KBr): νmax 580, 724, 747, 774, 886, 1007, 1106, 1239, 1304, 1391, 1415, 1472, 1558, 1634, 2860, 2925, 3126 cm−1. Anal. Calcd for C12H10INO2: C, 44.06; H, 3.08; N, 4.28. Found: C, 44.05; H, 3.31; N, 4.08.
N-Methoxymethyl-N-phenyl-2-(3-iodo)furamide (2c)
By the same procedure used for the preparation of 1c, 2c (80.8 mg, 73%) was obtained from 2a (96.9 mg, 0.310 mmol), yellow oil. 1H-NMR (400 MHz, CDCl3) δ: 3.50 (3H, s, OMe), 5.24 (2H, s, CH2), 6.48 (1H, d, J = 1.6 Hz, 4-H), 7.03 (1H, d, J = 2.0 Hz, 5-H), 7.15-7.17 (2H, m, 2’, 6’-H), 7.23-7.27 (1H, m, 4’-H), 7.28-7.33 (2H, m, 3’, 5’-H). 13C-NMR (100 MHz, CDCl3) δ: 56.7, 71.5, 79.8, 120.1, 126.5, 127.1, 129.0, 141.9, 144.4, 146.4, 160.3. IR (neat): νmax 598, 700, 749, 887, 912, 957, 1069, 1097, 1194, 1296, 1379, 1495, 1595, 1651, 2937 cm−1. Anal. Calcd for C13H12INO3: C, 43.72; H, 3.39; N, 3.92. Found: C, 44.03; H, 3.21; N, 3.75.
N-(2-Iodophenyl)-3-furamide (4a)3c,5a
A mixture of furan-3-carboxylic acid (4.01 g, 35.8 mmol), SOCl2 (11.5 mL, 159 mmol), DMF (0.28 mL, 3.62 mmol), and CH2Cl2 (35 mL) was heated for 1 h under reflux. After the volatile materials were removed in vacuo, a solution of 2-iodoaniline (10.4 g, 47.5 mmol), Et3N (6.76 mL, 48.5 mmol) in CH2Cl2 (95 mL) was dropwise added at 0 oC. The mixture was allowed to warm to rt and stirred for 2 h. After cooling to 0 oC, the mixture was acidified by a 10% HCl aqueous solution and extracted with CH2Cl2. The organic layer was successively washed with water, a 10% NaOH aqueous solution, and brine. The solution was dried over MgSO4 and evaporated to give a residue which was recrystallized from MeOH. A yellow ocher solid of 4a (10.8 g, 96%) was obtained, mp 94.5-95.5 ˚C (MeOH) [lit.5a mp 93-94 ˚C (diisopropyl ether), lit.3c mp 95-97 ˚C]. 1H-NMR (400 MHz, CDCl3) δ: 6.80 (1H, dd, J = 1.2, 2.0 Hz, 4-H), 6.88 (1H, ddd, J = 1.2, 7.6, 8.0 Hz, 4’-H or 5’-H), 7.39 (1H, ddd, J = 1.2, 7.6, 8.0 Hz, 4’-H or 5’-H), 7.52 (1H, t, J = 1.6 Hz, 5-H), 7.80 (1H, dd, J = 1.6, 8.0 Hz, 3’-H or 6’-H), 7.89 (1H, s, NH), 8.10 (1H, dd, J = 1.2, 1.6 Hz, 2-H), 8.39 (1H, dd, J = 1.2, 8.4 Hz, 3’-H or 6’-H). 13C-NMR (100 MHz, CDCl3) δ: 90.2, 108.4, 121.9, 123.1, 126.1, 129.6, 138.1, 138.9, 144.4, 145.5, 160.5. IR (KBr) νmax 748, 860, 1015, 1070, 1161, 1323, 1433, 1516, 1578, 1659, 2300, 3150, 3317 cm−1. Anal. Calcd for C11H8INO2: C, 42.20; H, 2.58; N, 4.47. Found: C, 42.47; H, 2.80; N, 4.41.
N-(2-Iodophenyl)-N-methyl-3-furamide (4b) 3c,5a
By the same procedure used for the preparation of 1b, 4b (223 mg, 74%) was obtained from 4a (287 mg, 0.917 mmol), a brown solid, mp 90.1-90.5 ˚C (AcOEt) [lit.5a mp 81-83 ˚C (diisopropyl ether), lit.3c mp 80-82 ˚C]. 1H-NMR (400 MHz, CDCl3) δ: 3.32 (3H, s, NMe), 6.20 (1H, s, 4-H), 6.79 (1H, s, 5-H), 7.12 (1H, ddd, J = 1.6, 7.6, 7.6 Hz, 4’-H or 5’-H), 7.16 (1H, s, 2-H), 7.30 (1H, dd, J = 1.2, 8.0 Hz, 3’-H or 6’-H), 7.42 (1H, ddd, J = 1.6, 7.6, 7.6 Hz, 4’-H or 5’-H), 7.93 (1H, dd, J = 1.6, 7.6 Hz, 3’-H or 6’-H). 13C-NMR (100 MHz, CDCl3) δ: 37.1, 100.0, 111.0, 121.9, 129.8, 130.0, 130.3, 140.4, 142.3, 145.3, 146.3, 163.1. IR (KBr): νmax 572, 598, 750, 739, 842, 876, 1009, 1153, 1359, 1391, 1426, 1469, 1509, 1565, 2921, 3137 cm−1. Anal. Calcd for C12H10INO2: C, 44.06; H, 3.08; N, 4.28. Found: C, 43.98; H, 3.29; N, 4.15.
N-(2-Iodophenyl)-N-methoxymethyl-3-furamide (4c)
By the same procedure used for the preparation of 1c, 4c (1.14 g, 87%) was obtained from 4a (1.11 g, 3.54 mmol), brown oil. 1H-NMR (400 MHz, CDCl3) δ: 3.51 (3H, s, OMe), 4.53 (1H, d, J = 10.0 Hz), 5.76 (1H, d, J = 9.6 Hz), 6.28 (1H,s), 6.72 (1H, s), 7.15 (1H, t, J = 7.6 Hz), 7.20 (1H, s), 7.35-7.37 (1H, m), 7.45 (1H, dt, J = 1.2, 8.0, 7.6 Hz, 4’-H or 5’-H), 7.95 (1H, dd, J = 1.2 Hz, 8.0 Hz, 3’-H or 6’-H). 13C-NMR (100 MHz, CDCl3) δ: 57.2, 79.1, 100.9, 111.2, 121.6, 129.7, 130.6, 131.6, 140.2, 142.4, 143.5, 145.7, 163.7. IR (neat) νmax 598, 729,750, 876, 1020, 1076, 1107, 1205, 1315, 1381, 1470, 1508, 1651, 2937 cm−1. Anal. Calcd for C13H12INO3: C, 43.72; H, 3.39; N, 3.92. Found: C, 43.47; H, 3.69; N, 3.94.
2-Iodofuran-3-carboxylic acid10
A solution of furan-3-carboxylic acid (4.41 g, 39.3 mmol) in THF (40 mL) was dropwise added to a solution of nBuLi (55.0 mL, 9.07 mol, 1.65 M in hexane) in THF at -78 oC. The mixture was allowed to warm to rt and stirred for 30 min. After cooling to -78 oC, a solution of I2 (11.0 g, 43.3 mmol) in THF (60 mL) was dropwise added to the mixture, then the mixture was warmed to rt and allowed to stand for 2 h. After a 10% HCl aqueous solution was added to acidify the mixture, an extractive work-up with Et2O was carried out. The organic layer was successively washed with Na2S2O3 and brine, then dried over MgSO4. After evaporation, the resulting residue was subjected to silica gel column chromatography with AcOH/1,1,2,2-tetrachloroethane (1/100) to give a colorless solid of the title compound (5.77 g, 62%), mp 168.2-170.0 ˚C (CHCl3) [lit.10 mp 148-150 ˚C]. 1H-NMR (400 MHz, CDCl3) δ: 6.79 (1H, d, J = 2.0 Hz, 4-H), 7.61 (1H, d, J = 2.0 Hz, 5-H). 13C-NMR (100 MHz, CDCl3) δ: 99.9, 112.9, 123.6, 148.7, 167.9. IR (KBr): νmax 741, 889, 1180, 1312, 1501, 1564, 1690 cm−1. Anal. Calcd for C5H3IO3: C, 25.23; H, 1.27. Found: C, 25.32; H, 1.45.
N-Phenyl-3-(2-iodo)furamide (5a)
A mixture of 2-iodofuran-3-carboxylic acid (1.01 g, 4.24 mmol), aniline (0.460 mL, 5.04 mmol), EDC (1.22 g, 6.36 mmol), DMAP (258 mg, 2.11 mmol), and CH2Cl2 (20 mL) was stirred for 30 min at rt. The mixture was successively washed with a 10% HCl, a 10% NaOH aqueous solution, and brine, then dried over MgSO4, and evaporated. The resulting residue was subjected to silica gel column chromatography with CH2Cl2/ hexane (1/8) to give 5a (1.25 g, 94%), a colorless solid, mp 140.8-142.0 ˚C (CH2Cl2). 1H-NMR (400 MHz, CDCl3) δ: 6.82 (1H, d, J = 2.4 Hz, 4-H), 7.16 (1H, dt, J = 0.8, 7.0 Hz, 4’-H), 7.37 (2H, t, J = 7.0 Hz, 3’, 5’-H), 7.62-7.64 (2H, m, 2’, 6’-H), 7.65 (1H, d, J = 2.4 Hz, 5-H), 7.82 (1H, s, NH). 13C-NMR (100 MHz, CDCl3) δ: 92.8, 112.1, 120.2, 124.9, 127.6, 129.2, 137.5, 148.6, 159.6. IR (KBr): νmax 583, 598, 687, 752, 804, 889, 1051, 1161, 1325, 1441, 1479, 1520, 1560, 1595, 1651, 2359, 3101, 3323 cm−1. Anal. Calcd for C11H8INO2: C, 42.20; H, 2.58; N, 4.47. Found: C, 42.28; H, 2.44; N, 4.56.
N-Methyl-N-phenyl-3-(2-iodo)furamide (5b)
By the same procedure used for the preparation of 1b, 5b (107 mg, 98%) was obtained from 5a (104 mg, 0.332 mmol), a colorless solid, mp 130.8-132.7 ˚C (AcOEt). 1H-NMR (400 MHz, CDCl3) δ: 3.45 (3H, s, NMe), 5.63 (1H, s), 7.13 (2H, dd, J = 1.2, 8.2 Hz), 7.24-7.27 (2H, m), 7.30-7.34 (2H, m). 13C-NMR (100 MHz, CDCl3) δ: 38.0, 95.0, 112.1, 127.1, 127.3, 127.4, 129.4, 143.9, 147.0, 163.6. IR (KBr): νmax 557, 600, 700, 746, 766, 847, 887, 970, 1040, 1146, 1304, 1371, 1493, 1568, 1597, 1638, 2934, 3146 cm−1. Anal. Calcd for C12H10INO2: C, 44.06; H, 3.08; N, 4.28. Found: C, 44.37; H, 2.89; N, 4.16.
N-Methoxymethyl-N-phenyl-3-(2-iodo)furamide (5c)
By the same procedure used for the preparation of 1c, 5c (2.00 g, 88%) was obtained from 5a (2.00 g, 6.39 mmol), yellow oil. 1H-NMR (400 MHz, CDCl3) (mixture of isomers based on the amide bond) δ: 3.49 (3H, s, OMe), 5.22 (s), 5.66 (brs), 7.17 (2H, m), 7.24-7.33 (4H, m). 13C-NMR (100 MHz, CDCl3) δ: 56.8, 79.7, 96.1, 112.0, 126.9, 127.7, 127.8, 129.4, 141.9, 147.1, 164.5. IR (neat): νmax 610, 702, 749, 887, 912, 1043, 1072, 1113, 1209, 1304, 1379, 1485, 1595, 1651 cm−1. Anal. Calcd for C13H12INO3: C, 43.72; H, 3.39; N, 3.92. Found: C, 43.93; H, 3.46; N, 3.70.

Typical procedure of the Pd-mediated coupling reaction (Table 1, Entry 2)
5-Methylfuro[2,3-c]quinolin-4(5H)-one (3b)3b
A mixture of 1b (50.2 mg, 0.153 mmol), Pd(OAc)2 (10.9 mg, 0.0486 mmol), Ph3P (24.5 mg, 0.0934 mmol), NaOAc (25.1 mg, 0.306 mmol), and DMF (2.5 mL) was heated for 4 h at 170 oC. After an extractive work-up with CH2Cl2, the organic layer was washed with brine, dried over MgSO4, and evaporated to give a residue which was subjected to silica gel column chromatography with hexane/AcOEt (2/1). A reddish brown solid of 3b (15.7 mg, 51%) was obtained, mp 124.8-126.4 ˚C [lit.3b mp 140-142 ˚C (CHCl3)]. 1H-NMR (400 MHz, CDCl3) δ: 3.85 (3H, s, NMe), 7.08 (1H, d, J = 2.0 Hz, 1-H), 7.35 (1H, t, J = 7.2 Hz, 7-H or 8-H), 7.48 (1H, d, J = 8.4 Hz, 6-H or 9-H), 7.57 (1H, ddd, J = 2.0, 8.8, 8.0 Hz, 7-H or 8-H), 7.84 (1H, d, J = 1.6 Hz, 2-H), 7.87 (1H, dd, J = 1.6, 7.6 Hz, 6-H or 9-H). 13C-NMR (100 MHz, CDCl3) δ: 29.4, 105.9, 115.3, 116.5, 122.6, 124.5, 128.8, 129.4, 138.0, 142.4, 148.1, 153.8. IR (KBr): νmax 427, 597, 621, 744, 806, 1013, 1093, 1147, 1235, 1326, 1434, 1490, 1586, 1665, 2971, 2890, 3095 cm−1. Anal. Calcd for C12H9NO2: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.40; H, 4.66; N, 7.02.
5-(Methoxymethyl)furo[2,3-c]quinolin-4(5H)-one (3c)
A colorless solid, mp 128.4-130.0 ˚C (AcOEt). 1H-NMR (400 MHz, CDCl3) δ: 3.46 (3H, s, OMe), 5.87 (2H, s, CH2), 7.08 (1H, d, J = 2.0 Hz, 1-H), 7.35 (1H, t, J = 7.2 Hz, 7-H or 8-H), 7.54 (1H, ddd, J = 1.6, 8.0, 8.0 Hz, 7-H or 8-H), 7.68 (1H, d, J = 8.4 Hz, 6-H or 9-H), 7.84-7.87 (2H, m, 6-H or 9-H, 2-H). 13C-NMR (100 MHz, CDCl3) δ: 56.6, 73.1, 106.1, 116.5, 116.8, 123.2, 124.5, 129.1, 130.7, 137.3, 141.8, 148.8, 154.5. IR (KBr): νmax 598, 683, 752, 797, 897, 961, 1030, 1084, 1219, 1437, 1456, 1491, 1589, 1668, 2814, 3105 cm−1. Anal. Calcd for C13H11NO3: C, 68.11; H, 4.84; N, 6.11. Found: C, 67.90; H, 4.94; N, 6.10.
5-Methylfuro[3,2-c]quinolin-4(5H)-one (6b)2e,2f,2g,2h,3c,5a
A reddish brown solid, mp 126.5-128.5 ˚C (AcOEt-CH2Cl2) [lit.3c mp 126-128˚C, lit.2h mp 132-133 ˚C, lit.5a mp 132-134 ˚C (diisopropyl ether), lit.2g mp 134-135 ˚C, lit.2f mp 129-130 ˚C, lit.2e mp 132-134 ˚C]. 1H-NMR (400 MHz, CDCl3) δ: 3.77 (3H, s, NMe), 7.06 (1H, d, J = 2.4 Hz, 3-H), 7.29 (1H, t, J = 6.8 Hz, 7-H or 8-H), 7.42 (1H, d, J = 8.8 Hz, 6-H or 9-H), 7.53 (1H, ddd, J = 1.2, 8.0, 8.0 Hz, 7-H or 8-H), 7.61 (1H, d, J = 2.4 Hz, 2-H), 7.98 (1H, d, J = 8.0 Hz, 6-H or 9-H). 13C-NMR (100 MHz, CDCl3) δ: 29.6, 108.5, 113.3, 115.1, 115.5, 121.3, 122.4, 129.6, 138.2, 144.1, 155.2, 159.6. IR (KBr): νmax 669, 743, 964, 1022, 1105, 1124, 1231, 1319, 1360, 1439, 1504, 1585, 1649, 2926, 3121 cm−1. Anal. Calcd for C12H9NO2: C, 72.35; H,4.55; N, 7.03. Found: C, 72.09; H, 4.71; N, 6.98.
5-(Methoxymethyl)furo[3,2-c]quinolin-4(5H)-one (6c)
A colorless solid, mp 107.2-108.8 ˚C (AcOEt). 1H-NMR (400 MHz, CDCl3) δ: 3.45 (3H, s, OMe), 5.84 (2H, s, CH2), 7.07 (1H, d, J = 2.4 Hz, 3-H ), 7.34 (1H, dt, J = 1.2, 7.6 Hz, 7-H or 8-H), 7.55 (1H, ddd, J = 1.6, 8.0, 8.0 Hz, 7-H or 8-H), 7.64-7.68 (2H, m, 2-H, 6-H or 9-H), 8.01 (1H, dd, J = 1.2, 8.0 Hz, 6-H or 9-H). 13C-NMR (100 MHz, CDCl3) δ: 56.5, 73.1, 108.5, 113.5, 114.8, 116.3, 121.2, 123.1, 129.8, 137.5, 144.3, 155.9, 160.2. IR (KBr): νmax 756, 910, 1074, 1099, 1123, 1171, 1207, 1308, 1443, 1504, 1585, 1688, 2950, 3150 cm−1. Anal. Calcd for C13H11NO3: C, 68.11; H, 4.84; N, 6.11. Found: C, 67.89; H, 4.95; N, 6.10.

Removal of methoxymethyl group
Furo[2,3-c]quinolin-4(5H)-one (3a)2d
A mixture of 3c (51.4 mg, 0.224 mmol), conc.HCl (10 mL), and DME (10 mL) was stirred for 2 h at 85 oC. After neutralization with a 10% NaOH aqueous solution, the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, and evaporated to give a solid which was recrystallized from AcOEt. The colorless solid of 3a (28.2 mg, 68%) was obtained, mp 261.0-262.2 ˚C (EtOAc) [lit.2d mp 282.5-283 ˚C]. 1H-NMR (400 MHz, CDCl3) δ: 7.13 (1H, d, J = 2.0 Hz), 7.33 (1H, t, J = 8.0 Hz), 7.51 (1H, t, J = 8.0 Hz), 7.58 (1H, d, J = 8.4 Hz), 7.85 (1H, d, J = 7.6 Hz), 7.90 (1H, d, J = 1.6 Hz), 11.5 (1H, s, NH). 1H-NMR (400 MHz, DMSO-d6) δ: 7.26 (1H, t, J = 6.8 Hz), 7.42-7.47 (3H, m), 7.99 (1H, d, J = 7.6 Hz), 8.23 (1H, s), 11.9 (1H, s, NH). 13C-NMR (150 MHz, CDCl3) δ: 106.4, 116.2, 117.0, 123.2, 124.0, 128.9, 131.8, 136.4, 142.4, 148.7, 155.0. 13C-NMR (100 MHz, DMSO-d6) δ: 106.8, 115.5, 116.2, 122.3, 124.3, 128.7, 130.7, 136.9, 142.2, 149.3, 153.2. IR (KBr): νmax 449, 592, 654, 692, 750, 791, 887, 1059, 1213, 1337, 1435, 1489, 1558, 1670, 2363, 2883 cm−1. Anal. Calcd for C11H7NO2: C, 71.35; H, 3.81; N, 7.56. Found: C, 70.97; H, 4.00; N, 7.46.
Furo[3,2-c]quinolin-4(5H)-one (6a)1a,2a,2b,2c,2f,2h
A mixture of 6c (25.9 mg, 0.113 mmol), conc.HCl (3 mL), and DME (3 mL) was stirred for 1.5 h at 85 oC. After neutralization with a 10% NaOH aqueous solution, the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4, and evaporated to give a solid which was subjected to silica gel column chromatography with AcOEt /hexane (1/1). The colorless solid of 6a (17.8 mg, 85%) was obtained, mp (decomp.) 186.0-189.0 ˚C (AcOEt) [lit.2f,2h mp 249-250 ˚C (EtOH), lit.2c mp 245-247 ˚C, lit.2b mp 232-233 ˚C, lit.2a mp 247-249 ˚C. lit.1a mp 243-245 ˚C]. 1H-NMR (600 MHz, CDCl3) δ: 7.13 (1H, d, J = 1.8 Hz), 7.31 (1H, ddd, J = 1.2, 6.0, 6.0 Hz,), 7.48-7.53 (2H, m), 7.68 (1H, d, J = 1.8 Hz), 7.99 (1H, d, J = 7.8 Hz), 11.0 (1H, s, NH). 1H-NMR (400 MHz, DMSO-d6) δ: 7.06 (1H, d, J = 2.0 Hz, 3-H), 7.27 (1H, dt, J = 1.2, 7.6 Hz, 7-H or 8-H), 7.44 (1H, d, J = 8.0 Hz, 6-H or 9-H), 7.50 (1H, ddd, J = 1.2, 8.0, 7.6 Hz, 7-H or 8-H), 7.90 (1H, d, J = 7.6 Hz, 6-H or 9-H), 8.08 (1H, d, J = 2.0 Hz, 2-H), 11.7 (1H, s, NH). 13C-NMR (100 MHz, CDCl3) δ: 108.0, 112.5, 115.7, 116.5, 120.9, 123.1, 129.7, 136.7, 144.4, 157.0, 161.0. 13C-NMR (100 MHz, DMSO-d6) δ: 107.9, 111.4, 115.7, 116.2, 120.3, 122.5, 129.6, 137.2, 145.6, 155.5, 159.0. IR (KBr): νmax 461, 669, 752, 889, 1022, 1196, 1265, 1362, 1437, 1674, 2361, 2891, 3115 cm−1. HRMS (EI) Calcd for C11H7NO2 [M]+: 185.0477. Found: 185.0480.

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