SUPPORTING INFORMATION

Transcription

1 Y. Yamane, K. Sunahara, K. Okano, and A. Mori SUPPORTING INFORMATION Magnesium Bisamide-Mediated Halogen Dance of omothiophenes Yoshiki Yamane, Kazuhiro Sunahara, Kentaro Okano,* and Atsunori Mori Department of Chemical Science and Engineering, Kobe University 1-1 Rokkodai, Nada, Kobe (Japan) Table of Contents 1 General 2 Materials 3 Screening of Bases (Table 1) 4 Scope of Magnesium Amide-Mediated Halogen Dance (Table 2) 5 Synthesis of 2,3-Dibromothiophene Derivatives (Scheme 2) 6 Ester-Directed Halogen Dance (Table 4) 7 Synthesis of Functionalized Thiophenes (Scheme 4) 8 1 H NMR and 13 C NMR Spectra S1

2 Y. Yamane, K. Sunahara, K. Okano, and A. Mori 1 General Analytical thin layer chromatography (TLC) was performed on Merck 60 F 254 aluminum sheets precoated with a 0.25 mm thickness of silica gel. Melting points (m.p.) were measured on a Yanaco MP-J3 and are uncorrected. Infrared (IR) spectra were recorded on a uker Alpha with an ATR attachment (Ge) and are reported in wave numbers (cm 1 ). 1 H NMR (400 MHz) and 13 C NMR (100 MHz) spectra were measured on a JEOL ECZ400 spectrometer. Chemical shifts for 1 H NMR are reported in parts per million (ppm) downfield from tetramethylsilane with the solvent resonance as the internal standard (CHCl 3 : δ 7.26 ppm) and coupling constants are in Hertz (Hz). The following abbreviations are used for spin multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. Chemical shifts for 13 C NMR are reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl 3 : δ ppm, CD 3 OD: δ ppm). High-resolution mass spectra (HRMS) were performed on a JEOL JMS-T100LP AccuTOF LC-Plus (ESI) with a JEOL MS-5414DART attachment or a Thermo Scientific Exactive TM Plus Orbitrap mass spectrometer (ESI) with an AMR DART IC CUBE TM ion source (DART). 2 Materials Unless otherwise stated, all reactions were conducted in flame-dried glassware under an inert atmosphere of nitrogen. All work-up and purification procedures were carried out with reagent solvents in air. Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. Flash column chromatography was performed on Wakogel C-300 (45 75 µm, Wako Pure Chemical Industries, Ltd.). Recycling preparative SEC-HPLC was performed with LC-9201 (Japan Analytical Industry Co., Ltd.) equipped with preparative SEC column (JAI-GEL-2H). Anhydrous THF was purchased from Wako Pure Chemical Industries, Ltd. Freshly prepared ZnCl 2 TMEDA 1 and Pd(PPh 3 ) 2 4 were used in the following experiments. Mg(TMP) 2 2LiCl was prepared by the according procedure 3 and was titrated by Knochel s method. 4 3 Screening of Bases (Table 1) base S THF; S H 2 O 1 2a A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with 2,5-dibromothiophene (1) (121.2 mg, 0.50 mmol, 1.0 equiv). To the Schlenk tube was added a magnesium amide (0.60 mmol, 1.2 equiv) at room temperature. After stirring at room temperature for 3 h, the reaction mixture was treated with 1 M hydrochloric acid (3 ml). After (1) (a) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett. 1977, 6, ; b) Snégaroff, K.; Komagawa, S.; Chevallier, F.; Gros, P. C.; Golhen, S.; Roisnel, T.; Uchiyama, M.; Mongin, F. Chem. Eur. J. 2010, 16, (2) Coulson, D. R. Inorg. Synth. 1972, 13, (3) (a) Eaton, P. E.; Lee, C.-H.; Xiong, Y. J. Am. Chem. Soc. 1989, 111, (b) Okano, K.; Fujiwara, H.; Noji, T.; Fukuyama, T.; Tokuyama, H. Angew. Chem. Int. Ed. 2010, 49, (4) Clososki, G. C.; Rohbogner, C. J.; Knochel, P. Angew. Chem. Int. Ed. 2007, 46, S2

3 Y. Yamane, K. Sunahara, K. Okano, and A. Mori partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material. The yields of recovered 2,5-dibromothiophene (1) and 2,4-dibromothiophene (2a) were determined by 1 H NMR analysis using 1,1,2,2-tetrachloroethane (145.0 mg, 0.86 mmol) as an internal standard by comparing relative values of integration for the peaks observed at 6.84 ppm (two protons for 1) and 6.98 ppm (one proton for 2a) with that of 1,1,2,2-tetrachloroethane observed at 5.96 ppm. Reaction with LiTMP (Entry 2). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with 2,2,6,6-tetramethylpiperidine (101 µl, 0.60 mmol, 1.2 equiv) and anhydrous THF (5 ml). To the solution was added n-buli (1.64 M in n-hexane, 366 µl, 0.60 mmol) dropwise at 78 C. After the resulting solution was gradually raised to 0 C, and the solution was stirred at 0 C for 30 min and cooled to 78 C. To the solution was added 2,5-dibromothiophene (1) (122.0 mg, 0.50 mmol, 1.0 equiv). After stirring at 78 C for 5 min, the reaction mixture was treated with 1 M hydrochloric acid (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material. 4 Scope of Magnesium Amide-Mediated Halogen Dance (Table 2) S R Mg(TMP) 2 2LiCl THF rt, 3 h; E + E S R General Procedure (3,5-Dibromothiophen-2-yl)phenylmethanol (2b). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with 2,5-dibromothiophene (1) (122.5 mg, 0.50 mmol, 1.0 equiv). To the Schlenk tube was added Mg(TMP) 2 2LiCl (0.325 M, 0.60 mmol, 1.2 equiv) at room temperature. After stirring at room temperature for 3 h, the reaction mixture was treated with benzaldehyde (101 µl, 1.0 mmol, 2.0 equiv). After stirring at room temperature for 14 h, the reaction mixture was treated with 1 M hydrochloric acid (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane/ch 2 Cl 2 = 1:3) to provide the desired compound 2b (88.9 mg, mmol, 51%) as a pale yellow oil. R f = 0.49 (hexane/ch 2 Cl 2 = 1:3); IR (ATR, cm 1 ): 3348, 1448, 1309, 1285, 1144, 1032, 978, 817, 763, 699; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 5H), 6.90 (s, 1H), 6.09 (s, 1H), 2.45 (br s, 1H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 144.4, 141.4, 132.1, 128.8, 128.6, 126.4, 112.8, 107.3, 71.8; HRMS (DART + ) m/z: calcd. for C 11 H S, [M-OH] + ; found, S3

4 Y. Yamane, K. Sunahara, K. Okano, and A. Mori Ethyl 3,5-dibromothiophene-2-carboxylate (2c). The title compound was obtained in 42% yield (66.9 mg, mmol) as a yellow solid from 2,5-dibromothiophene (1) (122.8 mg, mmol, 1.0 equiv) and ethyl chloroformate (114 µl, 1.2 mmol, 2.4 equiv) according to the general procedure. Purification was performed by silica gel column chromatography (hexane/ch 2 Cl 2 = 4:1). R f = 0.47 (hexane/ch 2 Cl 2 = 1:3); M.p C (CHCl 3 ); IR (ATR, cm 1 ): 1725, 1698, 1511, 1420, 1312, 1279, 1236, 1074, 825, 756; 1 H NMR (400 MHz, CDCl 3 ): δ 7.08 (s, 1H), 4.35 (q, 2H, J = 7.2 Hz), 1.37 (t, 3H, J = 7.2 Hz); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 159.8, 135.4, 129.3, 119.7, 116.5, 61.8, 14.3; HRMS (DART + ) m/z: calcd. for C 7 H O 2 S, [M+H] + ; found, Allyl-3,5-dibromothiophene (2d). The title compound was obtained in 50% yield (143 mg, mmol) as a colorless oil from 2,5-dibromothiophene (1) (244.5 mg, 1.01 mmol, 1.0 equiv) and allyl iodide (219 µl, 2.4 mmol, 2.4 equiv) according to the general procedure. Purification was performed by silica gel column chromatography (hexane). R f = 0.75 (hexane); IR (ATR, cm 1 ): 1640, 1525, 1424, 1309, 990, 977, 921, 817, 787; 1 H NMR (400 MHz, CDCl 3 ): δ 6.89 (s, 1H), 5.89 (ddt, 1H, J = 17.2, 10.0, 6.4 Hz), (m, 2H), 3.46 (ddd, 2H, J = 6.4, 1.6, 1.2 Hz); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 139.2, 134.1, 132.1, 117.7, 110.1, 108.1, 33.8; HRMS (DART + ) m/z: calcd. for C 7 H S, [M+H] + ; found, ,4-Dibromo-2-methylthiophene (4a). The title compound was obtained in 37% yield (46.9 mg, mmol) as a pale yellow oil from 3,5-dibromo-2-methylthiophene (3) (128.6 mg, mmol, 1.0 equiv) according to the general procedure. Purification was performed by silica gel column chromatography (hexane). R f = 0.76 (hexane); IR (ATR, cm 1 ): 1515, 1451, 1313, 1166, 1132, 1021, 879, 839, 725; 1 H NMR (400 MHz, CDCl 3 ): δ 7.15 (s, 1H), 2.46 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 135.7, 120.0, 113.1, 113.0, 16.4; HRMS (DART + ) m/z: calcd. for C 5 H S, [M+H] + ; found, Allyl-3,4-dibromo-5-methylthiophene (4b). The title compound was obtained in 50% yield (65.6 mg, mmol) as a pale yellow oil from 3,5-dibromo-2-methylthiophene (3) (126.9 mg, mmol, 1.0 equiv) and allyl iodide (91 µl, 1.0 mmol, 2.0 equiv) according to the general procedure. Purification was performed by silica gel column chromatography (hexane). R f = 0.78 (hexane); IR (ATR, cm 1 ): 1640, 1531, 1425, 1379, 1298, 1015, 989, 919, 830, 739; 1 H NMR (400 MHz, CDCl 3 ): δ 5.89 (ddt, 1H, J = 16.4, 10.0, 6.8 Hz), (m, 2H), 3.52 (d, 2H, J = 6.8 Hz), 2.41 (s, 3H); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 134.6, 134.3, 132.7, 117.6, 112.1, 111.5, 34.6, 16.1; HRMS (DART + ) m/z: calcd. for C 8 H S, [M+H] + ; found, S4

5 Y. Yamane, K. Sunahara, K. Okano, and A. Mori 5 Synthesis of 2,3-Dibromothiophene Derivatives (Scheme 2) 5-Allyl-2,3-dibromothiophene (6). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with Mg(TMP) 2 2LiCl (0.372 M, 1.61 ml, 0.60 mmol, 1.2 equiv) at room temperature. After the resulting solution was cooled to 0 C, a mixture of 2,3-dibromothiophene (5) (55.5 µl, 0.50 mmol, 1.0 equiv) and allyl iodide (91.4 µl, 1.00 mmol, 2.0 equiv) in THF (0.10 ml) was added to the Schlenk tube. After stirring at 0 C for 3 min, the reaction mixture was treated with 1 M hydrochloric acid (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane) followed by preparative SEC-HPLC to provide the desired compound 6 (82.8 mg, mmol, 59%) as a colorless oil. R f = 0.71 (hexane); IR (ATR, cm 1 ): 1640, 1532, 1427, 1328, 1283, 1218, 1155, 989, 921, 829, 820; 1 H NMR (400 MHz, CDCl 3 ): δ 6.64 (t, 1H, J = 1.2 Hz), 5.90 (ddt, 2H, J = 16.8, 10.0, 6.4 Hz), (m, 2H), 3.47 (ddd, 1H, J = 6.4, 1.6, 1.2 Hz); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 144.6, 134.8, 127.6, 117.8, 113.3, 108.6, 34.7; HRMS (DART + ) m/z: calcd. for C 7 H S, [M+H] + ; found, Tributyl(4,5-dibromothiophen-2-yl)stannane (11). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with Mg(TMP) 2 2LiCl (0.340 M, 1.78 ml, 0.60 mmol, 1.2 equiv) at room temperature. After the resulting solution was cooled to 0 C, a mixture of 2,3-dibromothiophene (5) (56.3 µl, mmol, 1.0 equiv) and tributylstannyl chloride (276 µl, 1.02 mmol, 2.0 equiv) in THF (0.17 ml) was added to the Schlenk tube. After stirring at 0 C for 3 min, the reaction mixture was treated with 1 M hydrochloric acid (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane) followed by preparative SEC-HPLC to provide the desired compound 11 (250.1 mg mmol, 93%) as a colorless oil. R f = 0.65 (hexane); IR (ATR, cm 1 ): 2956, 2926, 2870, 2851, 1462, 1268, 986, 928, 875, 864, 824, 693, 665; 1 H NMR (400 MHz, CDCl 3 ): δ 6.91 (s, 1H), (m, 6H), 1.33 (tq, 6H, 7.6, 7.2 Hz), (m, 6H), 0.90 (t, 9H, J = 7.2 Hz); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 140.0, 137.5, 115.4, 115.2, 29.0, 27.4, 13.8, 11.2; HRMS (DART ) m/z: calcd. for C 16 H ClS 120 Sn, [M+Cl] ; found, ,5-Dibromo-N-phenylthiophene-2-carboxamide (12). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with Mg(TMP) 2 2LiCl (0.34 M, 1.78 ml, 0.60 mmol, 1.2 equiv) at room temperature. After the resulting solution was cooled to 0 C, 2,3-dibromothiophene (5) (120.4 mg, mmol, 1.0 equiv) was added to the Schlenk tube. After stirring at 0 C for 3 min, phenyl S5

6 Y. Yamane, K. Sunahara, K. Okano, and A. Mori isocyanate (108.2 µl, 1.00 mmol, 2.0 equiv) was added to the solution. After stirring at 0 C for 10 min, the reaction mixture was treated with 1 M hydrochloric acid (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by recrystallization and silica gel column chromatography (CH 2 Cl 2 ) to provide the desired compound 12 (75.7 mg, 0.21 mmol, 42%) as a colorless solid. R f = 0.39 (hexane/ch 2 Cl 2 = 1:4); M.p C (CH 2 Cl 2 /MeOH); IR (ATR, cm 1 ): 3269, 1642, 1601, 1542, 1443, 1411, 1323, 1264, 756, 689; 1 H NMR (400 MHz, CDCl 3 ): δ 7.57 (d, 2H, J = 8.4 Hz), (br s, 1H), 7.40 (s, 1H), 7.37 (dd, J = 8.4, 7.6 Hz, 2H), 7.18 (t, 1H, J = 7.6 Hz); 13 C{ 1 H} NMR (100 MHz, CD 3 OD): δ 160.3, 142.5, 139.2, 132.2, 129.9, 125.9, 122.0, 118.7, 115.4; HRMS (DART + ) m/z: calcd. for C 11 H NOS, [M+H] + ; found, ,3-Dibromo-5-(4-methoxyphenyl)thiophene (13). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with Mg(TMP) 2 2LiCl (0.28 M, 2.1 ml, 0.60 mmol, 1.2 equiv) at room temperature. After the resulting solution was cooled to 0 C, 2,3-dibromothiophene (5) (120.4 mg, 0.50 mmol, 1.0 equiv) was added to the Schlenk tube. After stirring at 0 C for 3 min, ZnCl 2 solution (1.0 M in diethyl ether, 550 µl, 0.55 mmol, 1.1 equiv) was added to the solution. After stirring at room temperature for 20 min, 4-iodoanisole (151.8 mg, 0.65 mmol, 1.3 equiv) and Pd(PPh 3 ) 4 (28.5 mg, 25 µmol, 5 mol%) were added to the solution. The resulting mixture was heated at 60 C for 8 h, at which time the reaction mixture was treated with 1 M hydrochloric acid (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane/et 2 O = 5:1) followed by preparative SEC-HPLC to provide 13 (132.3 mg, mmol, 76%) as a colorless solid. R f = 0.53 (hexane/et 2 O = 5:1); M.p C; IR (ATR, cm 1 ): 1601, 1499, 1456, 1441, 1311, 1288, 1259, 1182, 1112, 1031, 994, 951, 816; 1 H NMR (400 MHz, CDCl 3 ): δ 7.41 (d, 2H, J = 8.4 Hz), 6.99 (s, 1H), 6.92 (d, 2H, J = 8.8 Hz), 3.84 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 160.0, 145.4, 126.8, 125.5, 124.4, , , 108.9, 55.5; HRMS (DART + ) m/z: calcd. for C 11 H 81 9 OS, [M+H] + ; found, Synthesis of compound 13 using the in situ-trapping method. A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with 2,3-dibromothiophene (5) (120.9 mg, 0.50 mmol, 1.0 equiv) and ZnCl 2 solution (1.0 M in diethyl ether, 550 µl, 0.55 mmol, 1.1 equiv). After the resulting solution was cooled to 0 C, Mg(TMP) 2 2LiCl (0.28 M, 2.1 ml, 0.60 mmol, 1.2 equiv) was added to the Schlenk tube. After stirring at room temperature for 20 min, 4-iodoanisole (152.8 mg, 0.65 mmol, 1.3 equiv) and Pd(PPh 3 ) 4 (28.5 mg, 25 µmol, 5 mol%) were added to the solution. The resulting mixture was heated at 60 C for 8 h, at which time the reaction mixture was treated with hydrochloric acid (1 M, 3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column S6

7 Y. Yamane, K. Sunahara, K. Okano, and A. Mori chromatography (hexane/et 2 O = 5:1) followed by preparative SEC-HPLC to give 13 (123.3 mg, mmol, 71%) as a colorless solid. 6 Ester-Directed Halogen Dance (Table 4) Deuteration Experiments. Reaction with LiTMP (Entry 1). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with 2,2,6,6-tetramethylpiperidine (101 µl, 0.60 mmol, 1.2 equiv) and anhydrous THF (5 ml). To the solution was added n-buli (1.55 M in n-hexane, 387 µl, 0.60 mmol) dropwise at 78 C. After the resulting solution was gradually raised to 0 C, and the solution was stirred at 0 C for 30 min and then cooled to 78 C. To the resulting solution of bromothiophene 14 (116.5 mg, mmol, 1.0 equiv) was added to the Schlenk tube. After stirring at 78 C for 5 min, the reaction mixture was treated with D 2 O (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material. The yields were determined by 1 H NMR analysis using 1,1,2,2-tetrachloroethane (31.7 mg, mmol) as an internal standard by comparing relative values of integration for the peaks observed at 7.46 ppm (one proton for 14), 7.09 ppm (one proton for 14), 7.54 ppm (one proton for 15), and 7.07 ppm (one proton for 15) with that of 1,1,2,2-tetrachloroethane observed at 5.96 ppm. Reaction with TMPMgCl LiCl (Entry 2). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with TMPMgCl LiCl (1.0 M in THF/toluene, 600 µl, 0.60 mmol, 1.2 equiv) and an anhydrous THF (1.5 ml) at room temperature. After the resulting solution was cooled to 0 C, bromothiophene 14 (117.7 mg, mmol, 1.0 equiv) was added to the Schlenk tube. After stirring at 0 C for 30 min, the reaction mixture was treated with D 2 O (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material. The yields were determined by 1 H NMR analysis using 1,1,2,2-tetrachloroethane (40.5 mg, mmol) as an internal standard by comparing relative values of integration for the peaks observed at 7.46 ppm (one proton for 14), 7.09 ppm (one proton for 14), 7.54 ppm (one proton for 15), and 7.07 ppm (one proton for 15) with that of 1,1,2,2-tetrachloroethane observed at 5.96 ppm. Reaction with Mg(TMP) 2 2LiCl (Entry 3). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with Mg(TMP) 2 2LiCl (0.28 M, 2.1 ml, 0.60 mmol, 1.2 equiv) at room temperature. After the resulting solution was cooled to 0 C, bromothiophene 14 (117.6 mg, mmol, 1.0 equiv) was added to the Schlenk tube. After stirring at 0 C for 30 min, the reaction mixture was treated with D 2 O (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl S7

8 Y. Yamane, K. Sunahara, K. Okano, and A. Mori ether (3 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material. The yields were determined by 1 H NMR analysis using 1,1,2,2-tetrachloroethane (44.5 mg, mmol) as an internal standard by comparing relative values of integration for the peaks observed at 7.46 ppm (one proton for 14), 7.09 ppm (one proton for 14), 7.54 ppm (one proton for 15), and 7.07 ppm (one proton for 15) with that of 1,1,2,2-tetrachloroethane observed at 5.96 ppm. Ethyl 3-bromothiophene-2-carboxylate (15). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with Mg(TMP) 2 2LiCl (0.354 M, 1.69 ml, 0.60 mmol, 1.2 equiv) at room temperature. After the resulting solution was cooled to 0 C, bromothiophene 14 (116.6 mg, mmol, 1.0 equiv) was added to the Schlenk tube. After stirring at 0 C for 30 min, the reaction mixture was treated with 1 M hydrochloric acid (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane/ch 2 Cl 2 = 2:1) to provide the desired compound 15 (78.8 mg, mmol, 68%) as a pale yellow oil. R f = 0.33 (hexane/ch 2 Cl 2 = 2:1); IR (ATR, cm 1 ): 1719, 1699, 1506, 1417, 1353, 1280, 1237, 1091, 1071, 894, 766; 1 H NMR (400 MHz, CDCl 3 ): δ 7.46 (d, 1H, J = 5.4 Hz), 7.09 (d, 1H, J = 5.4 Hz), 4.37 (q, 2H, J = 7.2 Hz), 1.39 (t, 3H, J = 7.2 Hz); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 160.9, 133.1, 131.3, 127.8, 117.0, 61.6, 14.4; HRMS (DART + ) m/z: calcd. for C 7 H 79 8 O 2 S, [M+H] + ; found, Synthesis of Functionalized Thiophenes (Scheme 4) Ethyl 5-allyl-3-bromothiophene-2-carboxylate (20). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with Mg(TMP) 2 2LiCl (0.293 M, 4.09 ml, 1.2 mmol, 1.2 equiv) at room temperature. After the resulting solution was cooled to 0 C, bromothiophene 14 (225.9 mg, mmol, 1.0 equiv) was added to the Schlenk tube. After stirring at 0 C for 30 min, the reaction mixture was treated with allyl iodide (219 µl, 2.4 mmol, 2.5 equiv), and the resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with 1 M hydrochloric acid (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane/ch 2 Cl 2 = 2:1) to provide the allylated compound 20 (136 mg, mmol, 51%) as a pale yellow oil. R f = 0.35 (hexane/ch 2 Cl 2 = 2:1); IR (ATR, cm 1 ): 1720, 1697, 1525, 1453, 1282, 1241, 1073, 923, 828, 759; 1 H NMR (400 MHz, CDCl 3 ): δ 6.83 (t, 1H, J = 0.8 Hz), 5.93 (ddt, 1H, J = 16.8, 10.0, 6.8 Hz), (m, 2H), 4.33 (q, 2H, J = 7.2 Hz), (m, 2H), 1.37 (t, 3H, J = 7.2 Hz); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 160.9, 149.4, 134.4, 130.8, 125.7, 118.1, 116.7, 61.3, 34.5, 14.4; HRMS (DART + ) m/z: calcd. for C 12 H O 2 S, [M+H] + ; found, S8

9 Y. Yamane, K. Sunahara, K. Okano, and A. Mori Ethyl 3-bromo-5-phenylthiophene-2-carboxylate (22). A flame-dried 20-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with Mg(TMP) 2 2LiCl (0.33 M, 1.8 ml, 0.60 mmol, 1.2 equiv) at room temperature. After the resulting solution was cooled to 0 C, bromothiophene 14 (117.7 mg, 0.50 mmol, 1.0 equiv) was added to the Schlenk tube. After stirring at 0 C for 30 min, the solution was treated with ZnCl 2 TMEDA complex (164.7 mg, 0.65 mmol, 1.3 equiv). After stirring at room temperature for 20 min, iodobenzene (133.2 mg, 0.65 mmol, 1.3 equiv) and Pd(PPh 3 ) 4 (29.0 mg, 25 µmol, 5 mol%) were added to the solution. The resulting mixture was heated at 60 C for 11 h, at which time the reaction mixture was treated with saturated aqueous ammonium chloride (3 ml). After partitioned, the aqueous layer was extracted twice with diethyl ether (3 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude material, which was purified by silica gel column chromatography (hexane/diethyl ether = 2:1) followed by preparative SEC-HPLC to provide the desired product 20 in 57% yield (88.6 mg, mmol) as a pale yellow solid. R f = 0.38 (hexane/ch 2 Cl 2 = 2:1); M.p C (CHCl 3 ); IR (ATR, cm 1 ): 1685, 1439, 1334, 1291, 1089, 1016, 847, 761, 692; 1 H NMR (400 MHz, CDCl 3 ): δ (m, 2H), (m, 3H), 7.29 (s, 1H), 4.38 (q, 2H, J = 7.2 Hz), 1.41 (t, 3H, J = 7.2 Hz); 13 C{ 1 H} NMR (100 MHz, CDCl 3 ): δ 160.9, 149.3, 132.3, 129.5, 129.3, 128.6, , , 117.5, 61.5, 14.4; HRMS (DART + ) m/z: calcd. for C 13 H O 2 S, [M+H] + ; found, S9

10 abundance X : parts per Million : Proton S10

11 S11 (thousandths) X : parts per Million : Carbon

12 abundance X : parts per Million : Proton S12

13 (thousandths) X : parts per Million : Carbon S13

14 abundance X : parts per Million : Proton S14

15 S15 (thousandths) X : parts per Million : Carbon

16 S16 abundance X : parts per Million : Proton

17 (thousandths) X : parts per Million : Carbon S17

18 abundance X : parts per Million : Proton S18

19 (thousandths) X : parts per Million : Carbon S19

20 abundance X : parts per Million : Proton S20

21 S21 (thousandths) X : parts per Million : Carbon

22 H NMR (400 MHz, CDCl 3 ) S22 abundance S 11 Sn(n-Bu) 3 X : parts per Million : Proton

23 (thousandths) X : parts per Million : Carbon S23 13 C NMR (100 MHz, CDCl 3 ) Sn(n-Bu) 3 S 11

24 abundance S24 1 H NMR (400 MHz, CDCl 3 ) S 12 O H N X : parts per Million : Proton

25 C NMR (100 MHz, CD 3 OD) S25 (thousandths) S 12 O H N X : parts per Million : Carbon

26 H NMR (400 MHz, CDCl 3 ) S abundance S 13 OCH X : parts per Million : Proton

27 (thousandths) C NMR (100 MHz, CDCl 3 ) S 13 OCH 3 X : parts per Million : Carbon (thousandths) S27 X : parts per Million : Carbon

28 S28 abundance H NMR (400 MHz, CDCl 3 ) S CO 2 Et 15 X : parts per Million : Proton

29 (thousandths) X : parts per Million : Carbon S29 13 C NMR (100 MHz, CDCl 3 ) S CO 2 Et 15

30 H NMR (400 MHz, CDCl 3 ) S30 abundance S 20 CO 2 Et X : parts per Million : Proton

31 (thousandths) X : parts per Million : Carbon S31 13 C NMR (100 MHz, CDCl 3 ) S CO 2 Et 20

32 abundance X : parts per Million : Proton S32 1 H NMR (400 MHz, CDCl 3 ) S CO 2 Et 22

33 (thousandths) X : parts per Million : Carbon (thousandths) C NMR (100 MHz, CDCl 3 ) S CO 2 Et 22 S33 X : parts per Million : Carbon