Synthesis of Cyclic Thioethers through Tandem C(sp 3 )- S and C(sp 2 )-S Bond Formations from α,β -Dichloro Vinyl Ketones

Size: px

Start display at page:

Download "Synthesis of Cyclic Thioethers through Tandem C(sp 3 )- S and C(sp 2 )-S Bond Formations from α,β -Dichloro Vinyl Ketones"

Esther West
5 years ago
Views:

1 ynthesis of Cyclic Thioethers through Tandem C(sp 3 )- and C(sp 2 )- Bond Formations from α,β -Dichloro Vinyl Ketones Kyungsoo h,* Hyunjung Kim, Francesco Cardelli, Tamayi Bwititi, and Anna M. Martynow Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, Indiana oh@chem.iupui.edu Table of Contents: Experimental ection H NMR pectrum of (Z)-3b C NMR pectrum of (Z)-3b 25 1 H NMR pectrum of (E)-3b C NMR pectrum of (E)-3b 27 1 H NMR pectrum of (E)-3c C NMR pectrum of (E)-3c 29 1 H NMR pectrum of (E)-3d C NMR pectrum of (E)-3d 31 1 H NMR pectrum of (E)-3e C NMR pectrum of (E)-3e 33 1 H NMR pectrum of (Z)-3f C NMR pectrum of (Z)-3f 35 1 H NMR pectrum of (E)-3g C NMR pectrum of (E)-3g 37 1 H NMR pectrum of (Z)-3g C NMR pectrum of (Z)-3g 39 1 H NMR pectrum of (E)-3h C NMR pectrum of (E)-3h 41 1 H NMR pectrum of (E)-3i C NMR pectrum of (E)-3i 43 1 H NMR pectrum of (Z)-3i C NMR pectrum of (Z)-3i 45 1 H NMR pectrum of (Z)-3j C NMR pectrum of (Z)-3j 47 1 H NMR pectrum of (E)-3j C NMR pectrum of (E)-3j 49 1 H NMR pectrum of (Z)-3k C NMR pectrum of (Z)-3k 51 1 H NMR pectrum of (Z)-3l C NMR pectrum of (Z)-3l 53 1

2 1 H NMR pectrum of (Z)-3m C NMR pectrum of (Z)-3m 55 1 H NMR pectrum of (Z)-3n C NMR pectrum of (Z)-3n 57 1 H NMR pectrum of (Z)-3o C NMR pectrum of (Z)-3o 59 1 H NMR pectrum of 4c C NMR pectrum of 4c 61 1 H NMR pectrum of 4d C NMR pectrum of 4d 63 1 H NMR pectrum of 4e C NMR pectrum of 4e 65 1 H NMR pectrum of 4f C NMR pectrum of 4f 67 1 H NMR pectrum of 4h C NMR pectrum of 4h 69 1 H NMR pectrum of 4i C NMR pectrum of 4i 71 1 H NMR pectrum of 4j C NMR pectrum of 4j 73 1 H NMR pectrum of 4k C NMR pectrum of 4k 75 1 H NMR pectrum of 4m C NMR pectrum of 4m 77 1 H NMR pectrum of 4n C NMR pectrum of 4n 79 1 H NMR pectrum of 4o C NMR pectrum of 4o 81 1 H NMR pectrum of 4b C NMR pectrum of 4b 83 1 H NMR pectrum of 4g C NMR pectrum of 4g 85 1 H NMR pectrum of 4l C NMR pectrum of 4l 87 1 H NMR pectrum of C NMR pectrum of H NMR pectrum of C NMR pectrum of H NMR pectrum of 9a C NMR pectrum of 9a 93 1 H NMR pectrum of 9b C NMR pectrum of 9b 95 1 H NMR pectrum of 9c C NMR pectrum of 9c 97 2

3 Data of products Representative Procedure: Friedel-Crafts Acylation of Alkynes To a stirred suspension of aluminum chloride (1.53g, 11mmol) in dry dichloromethane (4ml) at 0 ο C, was added a mixture of 1-heptyne 1a (0.73ml, 10mmol) and chloroactetyl chloride (0.83ml, 10mmol) dropwise over 10 min. The cooling bath was removed and the reaction mixture was warmed up to ambient temperature over one hour. The mixture was poured into a mixture of brine and ice. The mixture was stirred for two hours at ambient temperature and extracted using dichloromethane (20ml 3). The combined organic layers were washed with brine and dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent 98/2 hexanes/diethyl ether) to give (Z)-alkene 3a (418mg, 25%) and (E)-alkene 3a (1.25g, 55%) as yellowish oil. The assignment of stereochemistry of the product was based on the work of Martens. 1 R f = 0.41 (3:97 Et 2 /Hex); (Z)-1,4-dichloronon-3-en-2-one (3a) IR (neat) 2957, 2931, 2862, 1692, 1599, 1461; 1 H NMR (500MHz, CD 3 ): 6.61 (1H, s), 4.08 (2H, s), 2.96 (2H, t, 7.6Hz), 1.60 (2H, m), 1.32 (4H, m), 0.89 (3H, t, 7.1Hz); 13 C NMR (125MHz, CD 3 ): 189.0, 161.1, 121.6, 49.0, 36.5, 30.9, 27.3, 22.3, 13.8; HRM calcd for C 9 H , found (MH + ) (E)-1,4-dichloronon-3-en-2-one (3a) R f = 0.17 (3:97 Et 2 /Hex); IR (neat) 2957, 2931, 2862, 1715, 1697, 1610, 1463; 1 H NMR (500MHz, CD 3 ): 6.48 (1H, s), 4.25 (2H, s), 2.47 (2H, t, 7.4Hz), 1.63 (2H, m), 1.30 (4H, m), 0.89 (3H, t, 7.1Hz); 1 Martens, H.; Hoornaert, G.; Toppet,. Tetrahedron 1973, 29,

4 13 C NMR (125MHz, CD 3 ): 189.2, 151.5, 120.6, 49.0, 41.6, 30.6, 26.9, 22.2, 13.8; HRM calcd for C 9 H , found (MH + ) (Z)-2,5-dichlorodec-4-en-3-one (3b) Yield: 62%((Z)-alkene (0.856g) and (E)-alkene (0.171g) as yellowish oil) R f = 0.54 (1:9 Et 2 /Hex); IR (neat) 2957, 2932, 2861, 1704, 1609; 1 H NMR (500MHz, CD 3 ): 6.60(1H, s), 4.43(1H, quartet, 6.5Hz), 2.47(2H, t, 7.5Hz), 1.71(2H, m), 1.60(3H, d, 7Hz), 1.35(4H, m), 0.92(3H, m); 13 C NMR (125MHz, CD 3 ): 191.4, 151.9, 119.2, 58.7, 41.6, 30.6, 26.9, 22.2, 19.8, 13.8; HRM calcd for C 10 H , found (MH + ) R f = 0.66 (1:9 Et 2 /Hex, yellowish oil); IR (neat) 2957, 2930, 2871, 1692, 1600; (E)-2,5-dichlorodec-4-en-3-one (3b) 1 H NMR (500MHz, CD 3 ): 6.68(1H, s), 4.34(1H, quartet, 6.85Hz), 2.96(2H, t, 6.7Hz), 1.64(5H, m), 1.35(4H, m), 0.91(3H, m); 13 C NMR 125MHz, CD 3 ): 191.8, 160.8, 122.0, 58.9, 36.5, 31.0, 27.4, 22.3, 20.0, 13.8; 4

5 (E)-1,5-dichlorodec-4-en-3-one (3c) Yield: 71%((Z)-alkene (0.476g) and (E)-alkene (1.09g) as yellowish oil) R f = 0.47 (3:7 Et 2 /Hex); IR (neat) 2958, 2931, 2861, 1696, 1600, 1364; 1 H NMR (500MHz, CD 3 ): 6.41(1H, s), 3.75(2H, t, 6.5Hz), 2.95(4H, m), 1.62(2H, m), 1.33(4H, m), 0.90(3H, m); 13 C NMR (125MHz, CD 3 ): 194.0, 158.5, 124.9, 46.5, 38.16, 36.2, 30.96, 27.4, 22.3, 13.8; HRM calcd for C 10 H , found (M + ) (E)-1,6-dichloroundec-5-en-4-one (3d) Yield: 62%((Z)-alkene (0.639g) and (E)-alkene (0.831g) as yellowish oil) R f = 0.80 (3:7 Et 2 /Hex); IR (neat) 2958, 2931, 2861, 1694, 1601; 1 H NMR (500MHz, CD 3 ): 6.42(1H, s), 3.58(2H, t, 6.5Hz), 2.93(2H, t, 7.5Hz), 2.65(2H, t, 7Hz), 2.08(2H, quintet, 6.5Hz), 1.61(2H, m), 1.33(4H, m), 0.90(3H, m); 13 C NMR (125MHz, CD 3 ): 196.5, 157.4, 125.3, 44.2, 41.1, 36.1, 31.0, 27.4, 26.5, 22.3, 13.9; HRM calcd for C 11 H , found (M + ) 5

6 (E)-1,7-dichlorododec-6-en-5-one (3e) Yield: 77%((Z)-alkene (0.668g) and (E)-alkene (1.27g) as yellowish oil) R f = 0.63 (3:7 Et 2 /Hex); IR (neat) 2956, 2931, 2871, 1701, 1665, 1611; 1 H NMR (500MHz, CD 3 ): 6.41(1H, s), 3.54(2H, t, 6.5Hz), 2.93(2H, t, 7.5Hz), 2.48(2H, t, 7Hz), 1.78(4H, m), 1.61(2H, m), 1.33(4H, m), 0.90(3H, m); 13 C NMR (125MHz, CD 3 ): 197.2, 157.2, 125.3, 44.5, 43.5, 36.0, 31.9, 31.0, 27.4, 22.3, 21.2, 13.9; HRM calcd for C 12 H , found (M + ) (Z)-1,4-dichloro-4-cyclohexylbut-3-en-2-one (3f) Yield: 64%((Z)-alkene (0.842g) and (E)-alkene (0.094g) as yellowish solids) m.p o C R f = 0.54 (3:7 Et 2 /Hex); IR (neat) 2931, 2855, 1719, 1703, 1698, 1605, 1450; 1 H NMR (500MHz, CD 3 ): 6.48(1H, d, 0.5Hz), 4.26(2H, s), 2.35(1H, tt, 11.5Hz, 3.5Hz), 1.92(2H, m), 1.89(2H, m), 1.73(1H, m), 1.41(4H, m), 1.20(1H, m); 13 C NMR (125MHz, CD 3 ): 189.7, 156.1, 119.0, 49.4, 49.1, 31.3, 25.8, 25.6; HRM calcd for C 10 H , found (MH + ) 6

7 (E)-1,4-dichloro-1-cyclohexylpent-1-en-3-one (3g) Yield: 61%((Z)-alkene (0.904g) and (E)-alkene (0.091g) as yellowish oil) R f = 0.82 (3:7 Et 2 /Hex); IR (neat) 2928, 2854, 1693, 1592, 1448; 1 H NMR (500MHz, CD 3 ): 6.62(1H, s), 4.35(1H, quartet, 7Hz), 3.81(1H, tt, 11.3Hz, 3.4Hz), 1.81(2H, m), 1.70(2H, m), 1.63(3H, d, 7Hz), 1.54(2H, m), 1.40(2H, m), 1.21(2H, m); 13 C NMR (125MHz, CD 3 ): 191.7, 165.9, 121.0, 59.0, 42.5, 30.6, 30.5, 25.6, 20.0; HRM calcd for C 11 H , found (M + ) R f = 0.70 (3:7 Et 2 /Hex, yellowish oil); IR (neat) 2931, 2855, 1702, 1603, 1448; (Z)-1,4-dichloro-1-cyclohexylpent-1-en-3-one (3g) 1 H NMR (500MHz, CD 3 ): 6.62(1H, s), 4.46(1H, quartet, 7Hz), 2.33(1H, tt, 11.4Hz, 3.15Hz), 1.92(2H, m), 1.85(2H, m), 1.70(1H, m), 1.62(3H, d, 6.85Hz), 1.43(2H, m), 1.32(2H, m), 1.2(1H, m); 13 C NMR (125MHz, CD 3 ): 191.9, 156.7, 117.5, 58.9, 49.4, 31.3, 25.8, 25.7, and 20.0; (E)-1,5-dichloro-1-cyclohexylpent-1-en-3-one (3h) Yield: 62%((Z)-alkene (0.374g) and (E)-alkene (0.747g) as yellowish oil) 7

8 R f = 0.73 (3:7 Et 2 /Hex); IR (neat) 2929, 2855, 1694, 1592, 1452; 1 H NMR (500MHz, CD 3 ): 6.33(1H, s), 3.83(1H, tt, 11.5Hz, 3.5Hz), 3.76(2H, t, 6.5Hz), 2.93(2H, t, 6.5Hz), 1.78(2H, m), 1.70(3H, m), 1.51(2H, m), 1.38(2H, m), 1.21(1H,m); 13 C NMR (125MHz, CD 3 ): 194.0, 163.6, 124.0, 46.6, 42.3, 38.2, 30.6, 25.6, 25.6; HRM calcd for C 11 H , found (M + ) (E)-1,6-dichloro-1-cyclohexylhex-1-en-3-one (3i) Yield: 90%((Z)-alkene (0.657g) and (E)-alkene (0.547g) as yellowish oil) R f = 0.73 (3:7 Et 2 /Hex); IR (neat) 2929, 2855, 1692, 1603, 1593, 1448; 1 H NMR (500MHz, CD 3 ): 6.36(1H, s), 3.83(1H, tt, 11.5Hz, 3.5Hz), 3.60(2H, t, 2Hz), 2.66(2H, t, 6.5Hz), 2.10(2H, quintet, 6.5Hz), 1.79(2H, m), 1.75(3H, m), 1.54(2H, m), 1.40(2H,m), 1.20(1H, m); 13 C NMR (125MHz, CD 3 ): 196.5, 162.4, 124.3, 44.2, 42.1, 41.2, 30.5, 26.5, 25.6, 25.6; HRM calcd for C 12 H , found ([M-H] + ) R f = 0.58 (3:7 Et 2 /Hex, yellowish oil); (Z)-1,6-dichloro-1-cyclohexylhex-1-en-3-one (3i) IR (neat) 2930, 2854, 1700, 1662, 1605, 1449; 8

9 1 H NMR (500MHz, CD 3 ): 6.27(1H, s), 3.63(2H, t, 6.3Hz), 2.83(2H, t, 6.95Hz), 2.28(1H, tt, 8.25Hz, 3.25Hz), 2.13(2H, quintet, 6.7Hz), 1.92(2H, m), 1.86(2H, m), 1.74(1H, m), 1.40(4H,m), 1.23(1H, m); 13 C NMR (125MHz, CD 3 ): 197.8, 152.3, 122.2, 49.1, 44.4, 40.8, 31.3, 26.6, 25.9, 25.7; (Z)-1,7-dichloro-1-cyclohexylhept-1-en-3-one (3j) Yield: 70%((Z)-alkene (0.635g) and (E)-alkene (0.576g) as yellowish oil) R f = 0.37 (1:5 Et 2 /Hex); IR (neat) 2931, 2855, 2849, 1707, 1662, 1606, 1449; 1 H NMR (500MHz, CD 3 ): 6.24(1H, d, 0.5Hz), 3.56(2H, t, 6Hz), 2.67(2H, t, 7Hz), 2.27(1H, tt, 11Hz, 3Hz), 1.91(9H, m), 1.39(5H, m); 13 C NMR (125MHz, CD 3 ): 198.6, 151.9, 122.2, 49.0, 44.6, 43.0, 31.9, 31.3, 25.9, 25.7, 21.2; HRM calcd for C 13 H , found (MH + ) R f = 0.54 (1:5 Et 2 /Hex, yellowish oil); IR (neat) 2929, 2854, 1691, 1593, 1448; (E)-1,7-dichloro-1-cyclohexylhept-1-en-3-one (3j) 1 H NMR (500MHz, CD 3 ): 6.35(1H, s), 3.84(1H, tt, 11.35Hz, 3.4Hz), 3.56(2H, t, 6.3Hz), 2.50(2H, t, 6.95Hz), 1.79(6H, m), 1.71(3H, m), 1.52(2H, m), 1.41(2H, m), 1.19(1H, m); 13 C NMR (125MHz, CD 3 ): 197.3, 162.2, 124.4, 44.5, 43.5, 42.0, 31.8, 30.6, 25.6, 25.6, 21.2; 9

10 (Z)-1,4-dichloro-4-phenylbut-3-en-2-one (3k) Yield: 70%((Z)-alkene (1.302g) as yellowish solids, mp o C) R f = 0.41 (3:7 Et 2 /Hex); IR (neat) 1706, 1692, 1588, 1573, 1489; 1 H NMR (500MHz, CD 3 ): 7.75(2H, m), 7.50(3H, m), 7.08(1H, s), 4.35(2H, s); 13 C NMR (125MHz, CD 3 ): 189.4, 146.8, 137.0, 131.3, 128.8, 127.5, 119.9, 49.1; HRM calcd for C 10 H , found (M + ) (Z)-1,4-dichloro-1-phenylpent-1-en-3-one (3l) Yield: 73%((Z)-alkene (0.924g) as yellowish oil) R f = 0.48 (1:9 Et 2 /Hex); IR (neat) 1700, 1588, 1575, 1445; 1 H NMR (500MHz, CD 3 ): 7.75(2H, m), 7.48(3H, m), 7.19(1H, s), 4.57(1H, quartet, 7Hz), 1.71(3H, d, 6.5Hz); 13 C NMR (125MHz, CD 3 ): 191.6, 147.3, 137.3, 131.1, 128.7, 127.5, 119.0, 59.2, 20.0; HRM calcd for C 11 H , found (MH + ) 10

11 (Z)-1,5-dichloro-1-phenylpent-1-en-3-one (3m) Yield: 80%((Z)-alkene (1.193g) and (E)-alkene (0.278g) as yellowish solids) m.p o C R f = 0.22 (1:9 Et 2 /Hex); IR (neat) 1696, 1655, 1588, 1572, 1490; 1 H NMR (500MHz, CD 3 ): 7.71(2H, m), 7.47(3H, m), 6.81(1H, s), 3.87(2H, t, 7Hz), 3.25(2H, t, 7Hz); 13 C NMR (125MHz, CD 3 ): 194.9, 144.1, 137.1, 130.9, 128.7, 127.4, 123.4, 46.7, 38.3; HRM calcd for C 11 H , found (MH + ) (Z)-1,6-dichloro-1-phenylhex-1-en-3-one (3n) Yield: 73%((Z)-alkene (1.77g) as yellowish oil) R f = 0.22 (1:9 Et 2 /Hex); IR (neat) 1694, 1658, 1590, 1574, 1445; 1 H NMR (500MHz, CD 3 ): 7.62(2H, m), 7.38(3H, m), 6.74(1H, s), 3.58(2H, t, 6Hz), 2.86(2H, t, 7Hz), 2.12(2H, quintet, 7Hz); 13 C NMR (125MHz, CD 3 ): 197.2, 143.2, 137.3, 130.7, 128.7, 127.3, 123.7, 44.4, 41.1, 26.6; HRM calcd for C 12 H , found (M + ) 11

12 (Z)-1,7-dichloro-1-phenylhept-1-en-3-one (3o) Yield: 84%((Z)-alkene (2.15g) as yellowish solids) m.p o C R f = 0.38 (3:7 Et 2 /Hex); IR (neat) 1696, 1657, 1590, 1574, 1490; 1 H NMR (500MHz, CD 3 ): 7.71(2H, m), 7.45(3H, m), 6.80(1H, s), 3.60(2H, m), 2.77(2H, m), 1.87(4H, m); 13 C NMR (125MHz, CD 3 ): 198.0, 142.8, 137.4, 130.7, 128.6, 127.3, 123.8, 44.6, 43.3, 31.9, 21.3; HRM calcd for C 13 H , found (M + ) Representative Procedure: Cyclization using NaH. xh 2 To a stirred sodium hydrosulfide hydrate (68-72% flakes, 89mg, 1.06mmol) at ambient temperature, was added the alkenes 3a (200mg, 0.90mmol) in acetone (2ml) dropwise. The reaction was complete in 5 min as evidenced by thin layer chromatography. The reaction mixture was diluted with diethyl ether (10ml) and filtered through Celite. After solvent removal under reduced pressure, the residue was purified by flash chromatography on silica gel (eluent 90/10 hexanes/diethyl ether) to give thiophen-3-one 4a as a yellowish oil (5.47g, 67%). 5-pentylthiophen-3(2H)-one (4a) R f = 0.20 (20:80 Et 2 /Hex); IR (neat) 2957, 2928, 2857, 1656, 1564, 1460; 12

13 1 H NMR (500MHz, CD 3 ): 6.00 (1H, s), 3.62 (2H, s), 2.61 (2H, t, 7.6Hz), 1.65 (2H, m), 1.34 (4H, m), 0.89 (3H, t, 6.6Hz); 13 C NMR (125MHz, CD 3 ): 202.8, 185.7, 120.9, 40.8, 33.9, 31.2, 28.3, 22.4, 13.9; HRM calcd for C 9 H , found (M + ) 6-pentyl-2H-thiopyran-4(3H)-one (4c) Yield: 74% (reaction performed at 50 o C for 3h, yellowish oil) R f = 0.66 (1:1 Et 2 /Hex); IR (neat) 2955, 2929, 2858, 1653, 1572; 1 H NMR (500MHz, CD 3 ): 6.07(1H, d, 1Hz), 3.17(2H, m), 2.65(2H, m), 2.37(2H, td, 7.5Hz, 0.5Hz), 1.62(2H, m), 1.35(4H, m), 0.90(3H, t, 7Hz); 13 C NMR (125MHz, CD 3 ): 194.4, 165.1, 121.7, 38.3, 36.8, 31.1, 28.4, 27.4, 22.3, 13.8; HRM calcd for C 10 H , found (M + ) Yield: 64% (yellowish oil) R f = 0.17 (1:5 Et 2 /Hex); IR (neat) 2956, 2927, 2857, 1655, 1578; (Z)-2-pentyl-6,7-dihydrothiepin-4(5H)-one (4d) 1 H NMR (500MHz, CD 3 ): 6.04(1H, s), 2.93(2H, t, 6.5Hz), 2.82(2H, td, 7Hz, 0.5Hz), 2.37(2H, td, 8Hz, 0.5Hz), 2.23(2H, quintet, 10Hz), 1.60(2H, quintet, 7.5Hz), 1.34(4H, m), 0.89(3H, t, 4.5Hz); 13 C NMR (125MHz, CD 3 ): 202.1, 166.6, 127.5, 41.6, 40.1, 37.6, 31.1, 30.7, 28.8, 22.3, 13.9; 13

14 HRM calcd for C 11 H , found (M + ) Yield: 55% (yellowish oil) R f = 0.24 (1:5 Et 2 /Hex); (Z)-8-pentyl-4,5-dihydro-2H-thiocin-6(3H)-one (4e) IR (neat) 2929, 2857, 1659, 1645, 1633, 1592; 1 H NMR (500MHz, CD 3 ): 5.93(1H, s), 2.87(2H, t, 5.5Hz), 2.70(2H, t, 6Hz, 0.5Hz), 2.27(2H, t, 8Hz, 7.5Hz), 2.03(2H, m), 1.90(2H, m), 1.62(2H, m), 1.32(4H, m), 0.90(3H, t, 6.5Hz); 13 C NMR (125MHz, CD 3 ): 206.7, 154.5, 123.1, 42.1, 40.3, 32.8, 31.1, 30.3, 29.1, 22.3, 21.5, 13.9; HRM calcd for C 12 H , found (M + ) Yield: 47% (yellowish oil) R f = 0.51 (1:1 Et 2 /Hex); 5-cyclohexylthiophen-3(2H)-one (4f) IR (neat) 2927, 2852, 1664, 1645, 1554, 1447; 1 H NMR (500MHz, CD 3 ): 6.03(1H, d, 1Hz), 3.62(2H, d, 0.5Hz), 2.58(1H, m), 1.99(2H, m), 1.86(2H, m), 1.76(1H, m), 1.44(5H, m); 13 C NMR (125MHz, CD 3 ): 203.0, 190.8, 119.0, 42.9, 40.0, 32.6, 25.9, 25.7; HRM calcd for C 10 H , found (M + ) 14

15 Yield: 66% (mp o C) R f = 0.43 (1:1 Et 2 /Hex); 6-cyclohexyl-2H-thiopyran-4(3H)-one (4h) IR (neat) 2927, 2852, 1652, 1565, 1448, 1325; 1 H NMR (500MHz, CD 3 ): 6.06(1H, d, 0.5Hz), 3.14(2H, m), 2.64(2H, m), 2.20(1H, tt, 11.5Hz, 3Hz), 1.85(6H, m), 1.37(4H, m); 13 C NMR (125MHz, CD 3 ): 194.7, 170.4, 119.8, 47.2, 37.1, 32.4, 27.2, 26.2, 25.7; HRM calcd for C 11 H , found (M + ) Yield: 64% m.p o C R f = 0.25 (1:5 Et 2 /Hex); IR (neat) 2926, 2852, 1654, 1572; (Z)-2-cyclohexyl-6,7-dihydrothiepin-4(5H)-one (4i) 1 H NMR (500MHz, CD 3 ): 6.06(1H, d, 0.5Hz), 2.91(2H, t, 6.5Hz), 2.82(2H, td, 0.5Hz, 7Hz), 2.24(3H, m), 1.85(4H, m), 1.71(1H, m), 1.35(4H, m), 1.19(1H, m); 13 C NMR (125MHz, CD 3 ): 202.6, 172.0, 125.7, 48.7, 41.6, 37.7, 32.7, 30.8, 26.3, 25.8; HRM calcd for C 12 H , found (M + ) 15

16 Yield: 51% (yellowish oil) R f = 0.21 (1:5 Et 2 /Hex); (Z)-8-cyclohexyl-4,5-dihydro-2H-thiocin-6(3H)-one (4j) IR (neat) 2957, 2930, 2871, 1693, 1600, 1445; 1 H NMR (500MHz, CD 3 ): 5.96(1H, s), 2.84(2H, m), 2.74(2H, m), 2.07(1H, tt, 11.5Hz, 3Hz), 1.98(2H, m), 1.91(4H, m), 1.80(2H, m), 1.78(1H, m), 1.35(5H, m); 13 C NMR (125MHz, CD 3 ): 207.2, 160.4, 122.0, 49.0, 41.7, 33.1, 33.1, 30.0, 26.5, 25.9, 21.8; HRM calcd for C 13 H , found (M + ) 5-phenylthiophen-3(2H)-one (4k) Yield: 50% m.p o C R f = 0.11 (1:5 Et 2 /Hex); IR (neat) 1687, 1658, 1643, 1552; 1 H NMR (500MHz, CD 3 ): 7.70(2H, m), 7.53(3H, m), 6.57(1H, m), 3.82(2H, s); 13 C NMR (125MHz, CD 3 ): 202.1, 178.3, 132.9, 132.1, 129.0, 126.6, 118.6, 40.6; HRM calcd for C 10 H , found (M + ) 16

17 6-phenyl-2H-thiopyran-4(3H)-one (4m) Yield: 98% m.p o C R f = 0.33 (1:1Et 2 /Hex); IR (neat) 1633, 1538, 1487; 1 H NMR (500MHz, CD 3 ): 7.63(2H, m), 7.47(3H, m), 6.47(1H, s), 3.31(2H, m), 2.77(2H, m); 13 C NMR (125MHz, CD 3 ): 194.5, 160.5, 137.3, 131.0, 128.8, 127.1, 120.9, 37.0, 27.4; HRM calcd for C 11 H , found (M + ) Yield: 61% m.p o C R f = 0.18 (1:5 Et 2 /Hex); IR (neat) 2922, 1646, 1550, 1488; (Z)-2-phenyl-6,7-dihydrothiepin-4(5H)-one (4n) 1 H NMR (500MHz, CD 3 ): 7.65(2H, m), 7.45(3H, m), 6.35(1H, s), 3.14(2H, t, 7Hz), 2.97(2H, t, 7Hz), 2.37(2H, quintet, 7Hz); 13 C NMR (125MHz, CD 3 ): 201.7, 163.7, 138.9, 130.6, 128.6, 128.1, 126.9, 41.6, 38.0, 31.6; HRM calcd for C 12 H , found (M + ) 17

18 (Z)-8-phenyl-4,5-dihydro-2H-thiocin-6(3H)-one (4o) Yield: 30% m.p o C R f = 0.38 (3:7 Et 2 /Hex); IR (neat) 2922, 2866, 1713, 1644, 1557, 1488; 1 H NMR (500MHz, CD 3 ): 7.60(2H, m), 7.40(3H, m), 6.26(1H, s), 3.04(2H, m), 2.89(2H, m), 2.06(4H, m); 13 C NMR (125MHz, CD 3 ): 205.6, 153.9, 140.0, 129.9, 128.5, 128.0, 124.8, 41.0, 34.2, 29.7, 22.0; HRM calcd for C 13 H , found (M + ) Representative Procedure: Cyclization Followed by Acetylation To a stirred sodium hydrosulfide hydrate (68-72% flakes, 216mg) at ambient temperature, was added the alkenes (200mg, 0.87mmol) in acetone (2ml) dropwise. The reaction was complete in 5 min as evidenced by thin layer chromatography. The reaction was diluted with diethyl ether (10ml) and filtered through Celite. After solvent removal under reduced pressure, the residue was re-dissolved in dry dichloromethane (6.7ml) at 0 ο C and pyridine (0.214ml, 2.62mmol), acetic anhydride (0.124ml, 1.31mmol) were added sequentially. After 1h, saturated solution of NH 4 (10ml) was added. The layers were separated and the aqueous phase was extracted with dichloromethane (20ml 3). The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent 5/1 hexanes/diethyl ether) to give thiophen-3-one 4b as a reddish oil (129mg, 64%). 2-methyl-5-pentylthiophen-3-yl ethanoate (4b) 18

19 Yield: 64% (yellowish oil) R f = 0.51 (1:1 Et 2 /Hex); IR (neat) 2928, 2857, 1768, 1366, 1205; 1 H NMR (500MHz, CD 3 ): 6.48(1H, s), 2.68(2H, t, 7.5Hz), 2.25(3H, s), 2.19(3H, s), 1.63(2H, m), 1.35(4H, m), 0.90(3H, m); 13 C NMR (125MHz, CD 3 ): 168.8, 142.0, 140.4, 121.4, 118.6, 31.2, 30.8, 30.4, 22.4, 20.6, 13.9, 11.0; HRM calcd for C 12 H , found (M + ) Yield: 63% (yellowish oil) R f = 0.28 (1:5 Et 2 /Hex); IR (neat) 2925, 2852, 1769, 1579, 1447; 5-cyclohexyl-2-methylthiophen-3-yl ethanoate (4g) 1 H NMR (500MHz, CD 3 ): 6.48(1H, d, 0.5Hz), 2.65(1H, m), 2.25(3H, s), 2.20(3H, s), 2.01(2H, m), 1.81(2H, m), 1.71(1H, m), 1.34(5H, m); 13 C NMR (125MHz, CD 3 ): 168.8, 146.6, 142.0, 120.9, 116.6, 39.5, 34.8, 26.31, 25.9, 20.6, 11.1; HRM calcd for C 13 H , found (M + ) 2-methyl-5-phenylthiophen-3-yl ethanoate (4l) Yield: 64% 19

20 m.p o C R f = 0.46 (1:5 Et 2 /Hex); IR (neat) 1758, 1596; 1 H NMR (500MHz, CD 3 ): 7.74(2H, m), 7.59(3H, m), 7.50(1H, s), 2.52(3H, s), 2.51(3H, s); 13 C NMR (125MHz, CD 3 ): 168.6, 143.5, 138.6, 134.1, 128.8, 127.5, 125.2, 124.1, 117.7, 20.6, 11.3; HRM calcd for C 13 H , found (M + ) 2-chloro-1-(2-chlorophenyl)ethanone (11) To a stirred solution of 2 -chloroacetophenone 10 (0.17ml, 1.30mmol) in hexane (0.9ml) and methanol (0.08ml) at 0 ο C was added 2 2 (0.07ml, 0.91mmol) dropwise and the mixture was stirred for 4h. Additional portion of 2 2 (0.07ml, 0.91mmol) and methanol (0.08ml) were added to the mixture at 0 ο C and stirred for another 4h. The reaction was then diluted with dichloromethane (10ml) and quenched with aqueous NaHC 3 (10ml). The aqueous layer was extracted with dichloromethane (20ml) and the combined organic layer was dried over magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent 5/1 hexanes/dichloromethane) to give the desired product 11 as a solid (240mg, 98%) m.p o C R f = 0.41 (1:1 Et 2 /Hex); IR (neat) 1710, 1433; 1 H NMR (500MHz, CD 3 ): 7.56(2H, m), 7.45(1H, m), 7.38(1H, m), 4.69(2H, s); 13 C NMR (125MHz, CD 3 ): 194.2, 136.4, 132.7, 131.4, 130.1, 130.0, 127.2, 48.5; HRM calcd for C 8 H , found (M + ) 20

21 benzo[b]thiophen-3(2h)-one (12) To a stirred sodium hydrosulfide hydrate (68-72% flakes, 175mg) at ambient temperature, was added the alkenes 11 (200mg, 1.06mmol) in acetone (2ml) dropwise. The reaction was complete in 5 min as evidenced by thin layer chromatography. The reaction was diluted with diethyl ether (10ml) and filtered through Celite. After solvent removal under reduced pressure, the residue was purified by flash chromatography on silica gel (eluent 1/1 hexanes/diethyl ether) to give thiophen-3-one 12 2 as a reddish oil (142mg, 89%). R f = 0.13 (1:1 Et 2 /Hex); IR (neat) 1693, 1589, 1469, 1433; 1 H NMR (500MHz, CD 3 ): 7.58(1H, m), 7.42(2H, m), 7.41(1H, m), 3.95(2H, s); 13 C NMR (125MHz, CD 3 ): 196.6, 137.7, 132.2, 131.4, 130.6, 129.9, 127.0, 41.0; Representative Procedure: Cyclization using NaH. xh 2 To a stirred sodium hydrosulfide hydrate (68-72% flakes, 89mg) in 2-methoxyethanol (16ml) at ambient temperature, was added the alkenes 3b (200mg, 0.90mmol) dropwise. The reaction was stirred for 1.5h then quenched with saturated NH 4 (aq). The layers were separated using ethyl acetate and the organic layer was dried over magnesium sulfate. The solvent was removed under reduced pressure then the residue was purified by flash chromatograph on silica gel (eluent 9/1 hexanes/diethyl ether) to give the product 9 (18mg). (The corresponding thiophen-3-one 4b is present in the crude 1 H NMR, but decomposes rapidly!) Yield: 20% (yellowish oil) R f = 0.15 (1:9 Et 2 /Hex); 3-methyl-6-pentyl-1,2-dithiin-4(3H)-one (9a) 2 a) Pradhan, T. K.; De, A.; Mortier, J. Tetrahedron 2005, 61, b) Mukherjee, C.; Kamila,.; De, A. Tetrahedron 2003, 59,

22 IR (neat) 2956, 2928, 2858, 1657, 1574, 1446; 1 H NMR (500MHz, CD 3 ): 6.12(1H, t, 1Hz), 3.46(1H, quartet, 7Hz), 2.40(2H, td, 8Hz, 0.5Hz), 1.63(2H, m), 1.51(3H, d, 7Hz), 1.34(4H, m), 0.91(3H, m); 13 C NMR (125MHz, CD 3 ): 189.2, 162.0, 122.1, 41.4, 38.1, 31.0, 28.6, 22.3, 13.8, 13.5; HRM calcd for C 10 H , found (M + ) Yield: 29% (yellowish oil) R f = 0.51 (1:7 Et 2 /Hex); IR (neat) 2927, 2851, 1654, 1573, 1446; 6-cyclohexyl-3-methyl-1,2-dithiin-4(3H)-one (9b) 1 H NMR (500MHz, CD 3 ): 6.11(1H, d, 0.5Hz), 3.45(1H, quartet, 7.1Hz), 2.22(1H, tt, 11.35Hz, 3.2Hz), 1.91(2H, m), 1.83(2H, m), 1.72(1H, m), 1.49(3H, d, 7.1Hz), 1.40(5H, m); 13 C NMR (125MHz, CD 3 ): 189.5, 167.3, 120.2, 47.3, 41.6, 32.7, 26.2, 25.6, 13.5; HRM calcd for C 11 H , found (M + ) Yield: 51% (yellowish oil) R f = 0.47 (1:7 Et 2 /Hex); IR (neat) 1650, 1555, 1444; 3-methyl-6-phenyl-1,2-dithiin-4(3H)-one (9c) 22

23 1 H NMR (500MHz, CD 3 ): 7.62(2H, m), 7.49(3H, m), 6.49(1H, s), 3.57(1H, quartet, 7.15Hz), 1.58(3H, d, 7.1Hz); 13 C NMR (125MHz, CD 3 ): 189.4, 158.7, 136.4, 131.4, 129.1, 127.7, 121.6, 41.8, 13.5; HRM calcd for C 11 H , found (MH + ) 23

Supplementary Note 1 : Chemical synthesis of (E/Z)-4,8-dimethylnona-2,7-dien-4-ol (4)

Supplementary Note 1 : Chemical synthesis of (E/Z)-4,8-dimethylnona-2,7-dien-4-ol (4) A solution of propenyl magnesium bromide in THF (17.5 mmol) under nitrogen atmosphere was cooled in an ice bath and