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1 Supporting Information An Approach to 3,6-Disubstituted 2,5-Dioxybenzoquinones via Two Sequential Suzuki Couplings. Three-step Synthesis of Leucomelone Xianwen Gan, Wei Jiang, Wei Wang,,,* Lihong Hu,,* Shanghai Research Center for Modernization of Traditional Chinese Medicine, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 199 Guoshoujing Road, Shanghai , People s Republic of China Department of Chemistry & Chemical Biology, University of New Mexico, Albuquerque, NM , USA School of Pharmacy, East China University of Science & Technology, 130 Mei-Long Road, Shanghai , People s Republic of China Table of Contents 1. General 2. Preparation of the 2,5-dibromo-3,6-dimethoxy-1,4-benzoquionone 3. Preparation of the 5-aryl-2-bromo-3,6-dimethoxy-1,4-benzoquionones 4. Preparation of the 3,6-aryl-2,5-dimethoxy-1,4-benzoquionones 5. Preparation of the 3,6-aryl-2,5-dimethoxy-1,4-benzoquionones (Bis-Suzuki reactions) 6. Synthesis of leucomelone S1

2 1. General All reactions were carried out using standard syringe and septa techniques. Commercially available reagents and solvents were used as purchased. Column chromatography (CC) was performed on silica gel H ( mesh) and RP-18 (20 45 µm). 1 H (300 MHz) and 13 C (75 MHz) NMR spectra were recorded on a Varian Mercury 300 spectrometer in the solvent indicated. Chemical shifts are reported in ppm relative to the internal reference. HREIMS were obtained on a Finnigan MAT-95 mass spectrometer and HRESIMS on a Micromass Q-Tof Global mass spectrometer. 2. Preparation of the 2,5-dibromo-3,6-dimethoxy-1,4-benzoquionone 2,5-Dibromo-3,6-dimethoxy-1,4-benzoquionone (3): 2,5-Dihydroxy-1,4-benzoquinone (14.0 g, 100 mmol) was stirred in MeOH (850 ml) with 30 ml of conc. HCl at room temperature overnight and the precipitation was filtrated and washed with cold MeOH. The precipitation was dried in vacuo to afford 13.6 g (81%) of 2,5-dimethoxybenzoquinone. NBS (18.0 g, 100 mmol) was slowly added to the mixture of 2,5-dimethoxylbenzoquinone (8.40 g, 50.0 mmol) and DMF (250 ml). The mixture was stirred for 15h at rt. H 2 O was added to the reaction mixture, the aqueous lay was extracted with EtOAc three times. The organic lay was washed with H 2 O (two times) and brine (two times), and dried over Na 2 SO 4. The evaporation of the organic phase gave the crude product, and the crude product was purified by silica gel column chromatography to afford 13.4 g (82%) of 3 as a solid; IR (KBr) max 1648, 1560, 1331, 1204, 1150 cm 1 ; 1 H NMR (CDCl 3, 300MHz) δ 4.26 (6H, s); 13 C NMR (CDCl 3, 75 MHz) δ 174.5, 156.2, 114.8, 62.2; HREIMS calcd. For C 8 H 6 O 4 Br , found Preparation of the 5-aryl-2-bromo-3,6-dimethoxy-1,4-benzoquinones General procedure for Suzuki cross-coupling of 2,5-dibromo-3,6-dimethoxy-1,4- benzoquionone (3) with boronic acids: A solution of 3 (0.10 mmol), boronic acid (0.14 mmol), PdCl 2 (dppf) (5 mol%) and K 2 CO 3 (0.20 mmol) in anhydrous dioxane (1.0 ml) was left to stir at 110 ºC for 24 h and then concentrated in vacuo. The residue was purified by column chromatography to afford the corresponding 5-aryl-2-bromo-3,6-dimethoxy-1,4-benzoquinones. 2-Bromo-3,6-dimethoxy-5-(4-methoxy)phenyl-1,4-benzoquinones (5a): IR (KBr) max 1656, 1583, 1514, 1325, 1252, 1128, 1047 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.23 (2H, d, J = 8.7 Hz), 6.95 (2H, d, J = 8.7 Hz), 4.22 (3H, s), 3.84 (3H, s), 3.82 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 181.6,177.2, 160.1, 156.8, 154.6, 132.0, 126.5, 121.7, 115.2, 113.7, 62.1, 61.8, 55.4; HRMS (EI) calcd. for C 15 H 13 O 5 Br , found Bromo-3,6-dimethoxy-5-(4-Benzyloxy)phenyl-1,4-benzoquinones (5b): IR (KBr) max 1655, 1578, 1321, 1254, 1122, 1051 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.41 (5H, m), 7.25 (2H, d, J = 8.1 Hz), 7.03 (2H, d, J = 8.1 Hz), 5.09 (2H, s), 4.22 (3H, s), 3.84 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 181.5, 177.2, 159.3, 156.7, 154.5, 136.7, 132.0, 128.7, 128.2, 127,6, 126.5, 121.9, 115.1, 114.5, 70.1, 62.1, 61.8; HRMS (EI) calcd. for C 21 H 17 O 5 Br , found Bromo-3,6-dimethoxy-5-(3-methoxy)phenyl-1,4-benzoquinones (5c): IR (KBr) max 1670, 1646, 1583, 1319, 1290, 1118, 1041 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.34 (1H, t, J = 8.1 Hz), 6.94 (1H, m), 6.81 (2H, m), 4.23 (3H, s), 3.87 (3H, s), 3.82(3H,s); 13 C NMR (75 MHz, CDCl 3 ): δ 181.2, 177.1, 159.3, 156.7, 154.8, 131.0, 129.2, 126.0, 122.9, 116.3, 114.8, 114.4, 62.2, 61.9, 55,4; HRMS (EI) calcd. for C 15 H 13 O 5 Br , found Bromo-3,6-dimethoxy-5-(4-methylthio)phenyl-1,4-benzoquinones (5d): IR (KBr) max 1656, S2

3 1578, 1315, 1259, 1124,1045 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.28 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 4.22 (3H, s), 3.85 (3H, s), 2.50 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 181.3, 177.1, 156.7, 154.7, 140.2, 131.0, 126.2, 126.0, 125.6, 115.1, 62.2, 62.0, 15.4; HRMS (EI) calcd. for C 15 H 13 O 4 SBr , found Bromo-3,6-dimethoxy-5-(2-methoxy)phenyl-1,4-benzoquinones (5e): IR (KBr) max 1668, 1585, 1491, 1317, 1267, 1108, 1041 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.40 (1H, m), 7.10 (1H, m), 7.01 (1H, m), 6.95 (1H, J = 8.7 Hz), 4.22 (3H, s), 3.78 (3H, s), 3.74 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 180.7, 177.1, (2C), 155.1, 131.7, 130.7, 123.0, 120.5, 119.5, 114.5, 111.0, 62.1, 61.2, 55.7; HRMS (EI) calcd. for C 15 H 13 O 5 Br , found Bromo-3,6-dimethoxy-5-(4-t-butyl)phenyl-1,4-benzoquinones (5f): IR (KBr) max 1664, 1585, 1327, 1132, 1049 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.44 (2H, J = 8.7 Hz), 7.21 (2H, J = 8.7 Hz), 4.22 (3H, s), 3.83 (3H, s), 1.34 (9H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 181.6, 177.3, 156.8, 154.9, 152.1, 130.3, 126.8, 126.7, 125.2, 115.1, 62.2, 62.0, 31.4; HRMS (EI) calcd. for C 18 H 19 O 4 Br , found Bromo-3,6-dimethoxy-5-phenyl-1,4-benzoquinones (5g): IR (KBr) max 1670, 1645, 1583, 1309, 1124, 1043 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.42 (3H, m), 7.26 (2H, m), 4.23 (3H, s), 3.82 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 181.3, 177.2, 156.7, 154.8, 130.6, 129.8, 129.0, 128.2, 126.4, 115.0, 62.2, 62.0; HREIMS calcd. For C 14 H 11 O 4 Br , found Bromo-3,6-dimethoxy-5-(4-bromo)phenyl-1,4-benzoquinones (5h): IR (KBr) max 1664, 1650, 1583, 1315, 1124, 1040 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.56 (2H, d, J = 8.4 Hz), 7.15 (2H, d, J = 8.4 Hz), 4.23 (3H, s), 3.90 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 180.9, 177.0, 156.7, 154.8, 132.2, 131.4, 128.6, 125.6, 123.4, 115.1, 62.2, 62.1; HRMS (EI) calcd. for C 14 H 10 O 4 Br , found Bromo-3,6-dimethoxy-5-(4-fluoro)phenyl-1,4-benzoquinones (5i): IR (KBr) max 1664, 1653, 1585, 1304, 1126, 1041 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.26 (2H, m), 7.12 (2H, m), 4.23 (3H, s), 3.87 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 181.2, 177.1, (d, J = Hz), 156.7, 154.9, (d, J = 8.2 Hz), 125.7, (d, J = 3.4Hz), (d, J = 21.6Hz), 115.1, 62.2, 62.0; HRMS (EI) calcd. for For C 14 H 10 O 4 FBr , found Bromo-3,6-dimethoxy-5-(3-trifluoromethoxy)phenyl-1,4-benzoquinones (5j): IR (KBr) max 1672, 1655, 1576, 1439, 1338, 1305, 1132, 1049 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.65 (1H, m), 7.55(2H, m), 7.46 (1H, m), 4.24 (3H, s), 3.94 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 180.7, 176.9, 156.7, 155.1, 134.0, (q, J = 32.2 Hz), 130.5, 128.6, (q, J = 3.7 Hz), (q, J = 3.7 Hz), 125.2, (q, J = Hz), 115.1, 62.3, 62.2; HRMS (EI) calcd. for C 15 H 10 O 4 F 3 Br , found Bromo-3,6-dimethoxy-5-(3-thiophene)-1,4-benzoquinones (5k): IR (KBr) max 1662, 1651, 1583, 1309, 1117, 1038 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.70 (1H, m), 7.34 (2H, m), 4.22 (3H, s), 3.97 (3H, s); 13 C NMR (75 MHz, CDCl 3 ) δ 181.2, 177.2, 157.0, 154.2, 129.5, 129.0, 128.9, 124.6, 122.6, 115.2, 62.1, 61.8; HRMS (EI) calcd. for C 12 H 9 O 4 SBr , found Preparation of the 3,6-aryl-2,5-dimethoxy-1,4-benzoquionones General procedure for Suzuki cross-coupling of 2-bromo-3,6-dimethoxy-5-(4-methoxy) phenyl- 1,4-benzoquinones with different boronic acids A solution of 5a (0.10 mmol), boronic acid (0.15 mmon), PdCl 2 (dppf) (2mol%) and CsF (0.20 mmol) in toluene (1.0 ml) was left to stir at 70 ºC for 12 h and then concentrated in vacuo. The residue was purified by column chromatography or crystallization to afford the S3

4 corresponding 3,6-aryl-2,5-dimethoxy-1,4-benzoquionones. 3,6-Di(4-methoxy)phenyl-2,5-dimethoxy-1,4-benzoquinone (6a): 1 IR (KBr) max 1649, 1606, 1589, 1510, 1300, 1254, 1182, 1051 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.30 (4H, d, J = 8.1 Hz), 6.96 (4H, d, J = 8.1 Hz), 3.85 (6H, s), 3.82 (6H, s); 13 C NMR (75 MHz, CDCl 3 ): δ (2C), (2C), (2C), (4C), (2C), (2C), (4C), 61.6 (2C), 55.4 (2C); HRMS (EI) calcd. for C 22 H 21 O , found (3-Methoxy)phenyl-2,5-dimethoxyl-6-(4-methoxy)phenyl-1,4-benzoquinone (6b): IR (KBr) max 1643, 1595, 1300, 1254, 1180, 1053 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.33 (4H, m), 6.95 (4H, m), 3.85 (3H, s), 3.83 (6H, s), 3.82 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 183.8, 183.6, 159.9, 159.2, 154.8, 154.6, 132.1, 131.6, 129.1, 126.6, 126.3, 123.1, 122.2, 116.3, 114.4,113.6, 61.7, 61.7, 55.4; HRMS (EI) calcd. for C 22 H 21 O , found (2-Methoxy)phenyl-2,5-dimethoxyl-6-(4-methoxy)phenyl-1,4-benzoquinone (6c): IR (KBr) max 1660, 1608, 1593, 1512, 1315, 1248, 1055 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.40 (1H, t, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.17 (1H, d, J = 7.5 Hz), 6.99 (4H, m), 3.84 (3H, s), 3.83 (3H, s), 3.82 (3H, s), 3.74 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 183.7, 183.0, 159.8, 157.3, 155.2, 155.1, 132.1, 131.8, 130.4, 126.2, 123.0, 122.4, 120.4, 120.1, 113.5, 111.0, 61.5, 60.9, 55.7, 55.4; HRMS (EI) calcd. for C 22 H 21 O , found (4-Methoxy)phenyl-2,5-dimethoxy-6-(4-t-butyl)phenyl-1,4-benzoquinone (6d): IR (KBr) max 1655, 1643, 1589, 1514, 1300, 1051 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.46 (2H, d, J = 8.1 Hz), 7.30 (4H, t, J = 8.1 Hz), 6.98 (2H, d, J = 8.1 Hz), 3.85 (3H, s), 3.84 (3H, s), 3.83 (3H, s), 1.36 (9H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 184.1,184.0, 160.0, 154.8, 154.6, 151.8, 132.2, 130.4, 127.2, 126.9, 126.8, 125.1, 122.3, 113.7, 61.8, 61.7, 55.5, 34.9, 31.5; HRMS (EI) calcd. for C 25 H 27 O , found (4-Methylthio)phenyl-2,5-dimethoxyl-6-(4-methoxy)phenyl-1,4-benzoquinone (6e): IR (KBr) max 1649, 1589, 1514, 1298, 1252, 1182, 1049 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.30 (6H, m), 6.96 (2H, d, J = 8.4 Hz), 3.85 (3H, s), 3.84 (3H, s), 3.81 (3H, s), 2.51 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 183.8, 183.6, 159.9, 154.7, 154.5, 139.7, 132.1, 131.1, 126.7, 126.5, 126.3, 125.5, 122.1, 113.6, 61.7, 61.6, 55.4, 15.4; HRMS (EI) calcd. for C 22 H 21 O 5 S , found (4-Methoxy)phenyl-2,5-dimethoxyl-6-phenyl-1,4-benzoquinone (6f): IR (KBr) max 1651, 1591, 1512, 1302, 1256, 1182, 1049 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.42 (3H, m), 7.33 (4H, m), 6.98 (2H, d, J = 8.4 Hz), 3.85 (3H, s), 3.84 (3H, s), 3.82 (3H, s); 13 C NMR (75 MHz, CDCl 3 ): δ 183.9, 183.6, 159.9, 154.8, 154.5, 132.1,130.7, 130.3, 128.7, 128.0, 126.7, 126.6,122.2, 113.6, 61.7, 61.6, 55.4; HRMS (EI) calcd. for C 21 H 18 O 5 Na , found (4-Fluoro)phenyl-2,5-dimethoxyl-6-(4-methoxy)phenyl-1,4-benzoquinone (6g): IR (KBr) max 1651, 1606, 1510, 1294, 1255, 1049 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.32 (4H, m), 7.13 (2H, t, J = 8.7 Hz), 6.98 (2H, d, J = 9.0 Hz); 13 C NMR (75 MHz, CDCl 3 ): δ 183.8, 183.6, (d, J = 247 Hz), 160.0, 154.9, 154.5, (d, J = 8.2 Hz), 132.1, 126.8, (d, J = 3.7 Hz), 126.0, 122.1, (d, J = 21.6 Hz), 113.7, 61.8, 61.7, 55.4; HRMS (EI) calcd. for C 21 H 17 O 5 FNa , found (4-Methoxy)phenyl-2,5-dimethoxy-6-(3-trifluoromethyl)phenyl-1,4-benzoquinone (6h): IR (KBr) max 1651, 1589, 1302, 1115, 1051 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.62 (2H, m), 7.55 (2H, m), 7.30 (2H, d, J = 8.4Hz), 6.97 (2H, d, J = 8.4Hz); 13 C NMR (75 MHz, CDCl 3 ): δ 183.7, 183.0, 160.1, 155.2, 154.5, 134.1, 132.1, 131.1, (q, J = 32.2 Hz),128.5, (q, J = 3.8Hz), 126.9, (q, J = 3.8Hz), (ov), (q, J = 270.6Hz), 113.7, 61.9, 61.7, 55.4; HRMS (EI) calcd. for C 22 H 18 O 5 F , found S4

5 3-(3-Thiophene)-2,5-dimethoxyl-6-(4-methoxy)phenyl-1,4-benzoquinone (6i): IR (KBr) max 1653, 1589, 1512, 1292, 1256, 1184, 1053 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.78 (1H, m), 7.42 (1H, m), 7.36 (1H, m), 7.29 (2H, d, J = 8.7 Hz), 6.97 (2H, d, J = 8.7 Hz); 13 C NMR (75 MHz, CDCl 3 ): δ 184.0, 183.6, 160.0, 154.7, 154.3, 132.1, 129.7, 129.5, 128.7, 126.6, 124.3, 122.8, 122.1, 113.7, 61.6, 61.5, 55.4; HRMS (EI) calcd. for C 19 H 17 O 5 S , found Preparation of the 3,6-aryl-2,5-dimethoxy-1,4-benzoquionones (Bis-Suzuki reaction) General procedure for Bis-Suzuki cross-coupling of 2,5-Dibromo-3,6-dimethoxy -1,4- benzoquionone with different boronic acids: A solution of 4 (0.10 mmol), boronic acid (0.25 mmol), PdCl 2 (dppf) (2mol%), CsF (0.20 mmol) and Ag 2 O (0.25 mmol) in toluene (1.0 ml) was left to stir at 70 ºC for 14 h and then concentrated in vacuo. The residue was purified by column chromatography or crystallization to afford the corresponding 3,6-aryl-2,5-dimethoxy-1,4-benzoquionones. 3,6-Diphenyl-2,5-dimethoxy-1,4-benzoquinone (7): 2 IR (KBr) max 1651, 1589, 1298, 1107, 1043 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.42 (6H, m), 7.33(4H, m), 3.82 (6H, m); 13 C NMR (75 MHz, CDCl 3 ): (2C), (2C), (4C), (2C), (2C), (4C), (2C), 61.7 (2C); HRMS (EI) calcd. for C 20 H 16 O 4 Na , found Synthesis of leucomelone 3-(3,4-Dimethoxy)phenyl-2,5-dimethoxyl-6-(4-Benzyloxy)phenyl-1,4-benzoquinone (8): IR (KBr) max 1660, 1603, 1594, 1510, 1290, 1254, 1107, 1041 cm 1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 7.40 (5H, m), 7.31 (2H, d, J = 8.7 Hz), 7.05 (2H, d, J = 8.7 Hz), 6.92 (2H, m), 5.10 (2H, s), 3.92 (3H, s), 3.39 (3H, s), 3.82 (6H, s); 13 C NMR (75 MHz, CDCl 3 ): δ (2C), 159.2, 154.7, 154.6, 149.4, 148.4, 136.8, 132.1, 128.7, 128.2, 127.6,126.7, 126.6, 123.7, 122.4, 114.4, 113.9, 110.7, 70.1, 61.6, 61.5, 56.1, 56.0; HRMS (EI) calcd. for C 29 H 26 O 7 Na , found (3,4-Dihydroxy)phenyl-2,5-dihydroxy-6-(4-hydroxy)phenyl-1,4-benzoquinone (leucomelone, 9): 3 The substrate 8 (0.1 mmol) was dissolved in dry CH 2 Cl 2 (2.0 ml) and cooled to -78 ºC and 0.32 ml of BBr 3 (1.0 M in CH 2 Cl 2 ) was added dropwise with stirring. The reaction mixture was stirred at -78 ºC till rt over 8 h. The reaction was terminated by careful dropwise addition of water. The layers were separated, the organic phase was washed with H 2 O, and the combined aqueous layers were evaporated to dryness. The residue was separated by RP-18 column (MeOH:H 2 O 35:65) to gave brown-violet solids. IR (KBr) max 3420, 1640, 1608, 1520, 1325, 1276, 1001 cm 1 ; 1 H NMR (300 MHz, CD 3 OD): δ 7.33 (2H, d, J = 9.0 Hz), 6.96 (1H, d, J = 1.8 Hz), 6.81 (4H, m); 13 C NMR (75 MHz, DMSO): δ (br, 4C), 155.8, (2C), 132.1, 123.2, 123.0, 121.7, 118.1, 114.6, 114.1, 113.3, 112.8; HRMS (EI) calcd. for C 18 H 13 O , found References (1) Elix, J. A.; Ernst-Russell, M. A. Aust. J. Chem. 1996, 49, (2) Cain, B. F. J. Chem. Soc. 1961, 936. (3) Zheng C.-J.; Sohn M.-J.; Kim W.-G. J. Antibiot. 2006, 59, 808. S5