Thionation using Fluorous Lawesson s Reagent

Transcription

1 UPPRTING INFRMATIN for Thionation using Fluorous Lawesson s Reagent Zoltán Kaleta,, Brian T. Makowski, Tibor oós, *, and Roman Dembinski *, ) Department of Chemistry, akland University, 2200 N. quirrel Rd., Rochester, Michigan , UA ) Institute of Biomolecular Chemistry, Chemical Research Center of Hungarian Academy of cience, P.. Box 17, 1525 Budapest, Hungary dembinsk@oakland.edu Table of Contents: General Information Experimental procedure for 1-f 8 Experimental procedure for f 8 -LR Experimental procedure for 2 Experimental procedure for 1-f 6 Experimental procedure for f 6 -LR Experimental procedure for 4a (with f 8 -LR) Experimental procedure for 4a (with f 6 -LR) Experimental procedure for 4b Experimental procedure for 6a Experimental procedure for 6b Experimental procedure for 8a Experimental procedure for 8b Experimental procedure for 10a Experimental procedure for 10b Experimental procedure for 12a Experimental procedure for 12b pectra rganic Letters 2006, 8, ol060208a

2 General Information. Commercial chemicals were treated as follows: DMF, distilled from CaH 2 and degassed (freeze and thaw) three times prior to use; THF, ether, hexanes distilled from Na/benzophenone. 4-Bromo-1-butene, 1,2-dichlorobenzene (TCI America), perfluorohexyl iodide (Fluorous Technologies Inc.), phosphorus pentasulfide (Acros rganics), 1-phenyl-1,4-pentanedione, phenol 99+%, 1,2-dibenzoylethane (Lancaster), N,N'-bis(p-toluoyl)hydrazine (Alfa Aesar), N'- acetylbenzohydrazide, N-(4-methylbenzoyl)glycine (4-methylhippuric acid) (Aldrich), p-dioxane (anhydrous, EMD Chemicals), silica gel (J. T. Baker, mesh), TLC plates Analtech GF, cat. number 2521 or Merck 60, cat. number 5715, alumina neutral Brockmann activity I, mesh (Fisher), were used as received. N-(1-Methyl-2-oxohexyl)benzamide (7a), N-[2-(4- methoxyphenyl)-2-oxoethyl]-4-methylbenzamide 1 (7b), 2',3',5'-tri--acetyl-2'-deoxyuridine 2 (11a), 3',5'-di--acetyl-5-iodo-2'-deoxyuridine 2 (11b), and heptadecafluorododecyl bromide 3 were prepared by known methods. Fluorous reverse phase (FRP) purification: A glass column ( cm) or a cartridge packed with Fluorochrom (ilicycle, fluorous reverse phase silica gel; cartridges iliabond Fluorochrom - ilicycle or FluoroFlash - Fluorous Technologies Inc. can be also used), was wetted with ether and washed with acetonitrile prior to use. The microwave reaction was carried out in an unmodified household microwave oven (amsung MW5351G, 1.2 kw) at atmospheric pressure. The NMR spectra were recorded on a Bruker DPX Avance 200 spectrometer (200 MHz for 1 H and 50 MHz for 13 C). IR spectra were recorded on a Bio Rad FT-175C spectrometer. Mass spectra and high resolution mass spectra were recorded on a VG ZAB2-EQ tandem mass high resolution spectrometer instrument or GC/M Hewlett Packard HP 6890 GC instrument with 5973 mass selective detector. Microanalyses were conducted by Atlantic Microlab. M.p. were recorded on a Büchi apparatus. 1-(5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-Heptadecafluorododecyloxy)benzene (1-f 8 ). H + Br (CF 2 ) 7 CF K 2 C C (CF 2 ) 7 CF 3 1 (a) Farouz-Grant, F.; P.. Portoghese, P.. J. Med. Chem. 1997, 40, (b) Rapoport, H.; Knudsen, C. G. J. rg. Chem. 1983, 48, (a) Chang, P. K.; Welch, A. D. J. Med. Chem. 1963, 6, (b) Esho, N.; Desaulniers, J.- P.; Davies, B.; Chui, H. M.-P. Rao, M..; Chow, C..; zafert,.; Dembinski, R. Bioorg. Med. Chem. 2005, 13, Wilson,. R.; Cayetano, V.; Yurchenko, M. Tetrahedron 2002, 58,

3 A round bottom flask (100 ml) was charged with phenol (0.660 g, 7.01 mmol), K 2 C 3 (2.900 g, mmol), and DMF (50 ml) under N 2 atmosphere. A vigorous stirring was established and the flask was placed in a 70 C oil bath. 5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12- Heptadecafluorododecyl bromide 3 (3.608 g, mmol) was added via syringe. After 12 h the mixture was cooled to an ambient temperature, and brine (40 ml) and ether (40 ml) were added. The aqueous layer was washed in a separatory funnel with ether (2 20 ml). The combined three organic layers were washed with brine (3 30 ml), saturated aqueous Na 2 C 3 (3 30 ml), and dried over Na 2 4. olvent was removed by rotary evaporation and the residue was recrystallized from methanol (20 ml) to give 1-f 8 as a white solid (2.629 g, mmol, 71%), mp C. Anal. Calcd for C 18 H 13 F 17 : C, 38.04; H, Found: C 38.09; H M (EI, 70 ev) m/z (rel intensity) 568 (M +, 1), 94 (PhH +, 100). IR (KBr) 2884, 1604, 1586, 1502, 1478, 1465, 1384, 1372, 1346, 1327, 1151, 1082, 1071, 1038, 1014, 954, 753, 694, 656 cm -1. NMR (CDCl 3 ): 1 H 7.21 (t, J = 7.9 Hz, 2H, C 6 H 5 ), (m, 3H, C 6 H 5 ), 3.92 (t, J = 5.5 Hz, 2H, CH 2 ), (m, 2H, CH 2 CF 2 ), (m, 4H, CH 2 CH 2 CH 2 CH 2 CF 2 ); 13 C{ 1 H} 159.0, 129.6, 121.0, 114.6, 67.2, 30.8 (t, J = 22 Hz), 28.9, ,4-Bis(4-(5,5,6,6,7,7,8,8,9,9,10,10,11,11,12,12,12-heptadecafluorododecyloxy)phenyl)- 1,3,2,4-dithiadiphosphetane 2,4-disulfide (f 8 -LR). 2 CF 3 (CF 2 ) 7 + P 2 5 o-c 6 H 4 Cl C CF 3 (CF 2 ) 7 P P (CF 2 ) 7 CF 3 A round bottom flask (10 ml) was charged with 1-f 8 (2.273 g, mmol), phosphorus pentasulfide ( g, mmol), and 1,2-dichlorobenzene (4 ml), under N 2 atmosphere. After establishing vigorous stirring the flask was heated at 170 C (oil bath). After 1 h the mixture became homogenous. After an additional 3 h the mixture was cooled to an ambient temperature. The precipitate was filtered off and washed with hexanes (3 5 ml) to give f 8 -LR as a pale yellow solid (0.264 g, mmol, 51%), mp C dec. The filtrate was placed on a short plug of silica gel (2 6 cm) and eluted with hexanes. Low boiling solvent was removed by rotary evaporation to afford the residual 1-f 8 in 1,2- dichlorobenzene. This material can be reused for the same synthesis. 3

4 f 8 -LR data: M (EI, 70 ev) m/z (rel intensity) 662 ([M/2] +, 95), 599 ([M/2-P] +, 7), 125 (100), 63 (P +, 36); HRM (EI, 70 ev) monomer calcd. for (C 18 H 12 F 17 P 2 ): , found: IR (KBr) 2958, 1592, 1562, 1498, 1471, 1409, 1371, 1310, 1295, 1259, 1096, 956, 829, 701, 644, 566 cm -1. NMR (THF-d 8 ): 1 H 8.48 (dd, J = 16.7, 8.7 Hz, 4H, C 6 H 4 ), 7.20 (dd, J = 8.7, 3.7 Hz, 4H, C 6 H 4 ), 4.20 (t, J = 5.6 Hz, 2H, CH 2 ), (m, 4H, CH 2 CF 2 ), (m, 8H, CH 2 CH 2 CH 2 CF 2 ); 13 C{ 1 H} 164.4, (d, J = 17.2 Hz), ipso not observed, (d, J = 18.8 Hz), 55.1, 31.3 (t, J = 21.7 Hz), 29.5, 18.2; 31 P{ 1 H} (But-3-en-1-yloxy)benzene 4 (but-3-en-1-yl phenyl ether, 2). H + Br Na ethanol 80 C A round bottom flask (100 ml) was charged with phenol (3.01 g, 32.0 mmol) and anhydrous ethanol (50 ml) under N 2 atmosphere. After establishing vigorous stirring, sodium (0.690 g, 30.0 mmol) was added slowly. After the sodium was totally dissolved, 4-bromo-1-butene (4.050 g, mmol) was added via syringe and the flask was placed in an 80 C oil bath. After 12 h the ph of the mixture was still basic, and 4-bromo-1-butene (2.025 g, mmol) was added via syringe. After 12 h the ph became neutral and the solvent was removed via rotary evaporation. Brine (40 ml) and ether (40 ml) were added, and the mixture was transferred to a separatory funnel. The aqueous layer was washed with ether (3 20 ml). The combined four organic layers were washed with brine (2 40 ml), saturated aqueous Na 2 C 3 (40 ml), and dried over Na 2 4. olvent was removed by rotary evaporation to give 2 as a colorless oil (2.00 g, 13.5 mmol, 45%). 1 H and 13 C NMR spectral data matched those previously reported. 4 1-(5,5,6,6,7,7,8,8,9,9,10,10,10-Tridecafluorodecyloxy)benzene (1-f 6 ). I + I(CF 2 ) 5 CF 3 AIBN 85 C (CF 2 ) 5 CF 3 (CF 2 ) 5 CF 3 LiAlH 4 ether 4 Westwell, A. D.; Williams, J. M. J. Tetrahedron 1997, 53,

5 A chlenk flask (25 ml) was charged under N 2 atmosphere with 2 (2.964 g, mmol), perfluorohexyliodide (9.811 g, mmol), and AIBN (0.131 g, mmol). The resulting mixture was degassed (freeze and thaw) three times. The flask was placed into a 85 C oil bath. Progress of the reaction was monitored by 1 H NMR. After completion, the volatiles were removed by rotary evaporation, and the crude iodide was used for further reaction. A 250 ml round bottom flask was charged with lithium aluminum hydride (3.04 g, 80.0 mmol) and ether (80 ml). Crude iodide diluted in ether (40 ml) was added dropwise with stirring. After 2 h water (3 ml) was added carefully, followed by NaH (15% solution in water, 3 ml) and water (9 ml). The resulting suspension was stirred for 1 h. The solid was filtered off, and the solvent was evaporated from the filtrate by rotary evaporation. The product was crystallized from methanol (20 ml) to give 1-f 6 as a white solid (3.00 g, 6.41 mmol, 32%), mp C. Calcd for C 18 H 13 F 17 : C, 41.04; H, Found: C 41.12; H M (EI, 70 ev) m/z (rel intensity) 468 (M +, 1), 94 (PhH +, 100). IR (KBr) 2958, 2881, 1602, 1587, 1499, 1477, 1386, 1367, 1144, 1083, 1041, 1011, 753, 692 cm -1. NMR (CDCl 3 ): 1 H 7.21 (t, J = 7.9 Hz, 2H, C 6 H 5 ), (m, 3H, C 6 H 5 ), 3.91 (t, J = 5.5 Hz, 2H, CH 2 ), (m, 2H, CH 2 CF 2 ), (m, 4H, CH 2 CH 2 CH 2 CH 2 CF 2 ); 13 C{ 1 H} 159.0, 129.6, 121.0, 114.6, 67.2, 30.8 (t, J = 22 Hz), 28.9, ,4-Bis(4-(5,5,6,6,7,7,8,8,9,9,10,10,10-tridecafluorodecyloxy)phenyl)-1,3,2,4- dithiadiphosphetane 2,4-disulfide (f 6 -LR). 2 CF 3 (CF 2 ) 5 + P 2 5 o-c 6 H 4 Cl C CF 3 (CF 2 ) 5 P P (CF 2 ) 5 CF 3 A 25 ml round bottom flask was charged with 1-f 6 (5.62 g, 12.0 mmol), phosphorus pentasulfide (0.454 g, 2.00 mmol), and 1,2-dichlorobenzene (8 ml) under N 2 atmosphere. After establishing vigorous stirring the flask was heated at 170 C (oil bath). After 1 h the mixture became homogenous and after an additional 3 h was cooled to an ambient temperature. The precipitate was filtered off and washed with hexanes (3 5 ml) to give f 6 -LR as a pale yellow solid (0.871 g, mmol, 39%), mp 184 C. 5

6 The filtrate was placed on a short plug of silica gel (2 6 cm), and eluted with hexanes. Low boiling solvent was removed by rotary evaporation to afford the residual 1-f 6 in 1,2- dichlorobenzene. This material can be reused for the same synthesis. f 6 -LR data: M (EI, 70 ev) m/z (rel intensity) 562 ([M/2] +, 100), 499 ([M/2-P] +, 10), 125 (90), 63 (P +, 67); HRM (EI, 70 ev) monomer calcd. for (C 16 H 12 F 13 P 2 ): , found: IR (KBr) 2958, 1591, 1497, 1471, 1409, 1367, 1311, 1295, 1261, 1184, 1144, 1097, 829, 698, 645, 567 cm -1. NMR (THF-d 8 ): 1 H 8.47 (dd, J = 16.8, 8.7 Hz, 4H, C 6 H 4 ), 7.20 (dd, J = 8.7, 3.7 Hz, 4H, C 6 H 4 ), 4.19 (t, J = 5.7 Hz, 4H, CH 2 ), (m, 4H, CH 2 CF 2 ), (m, 8H, CH 2 CH 2 CH 2 CF 2 ); 13 C{ 1 H} 164.6, (d, J = 17.2 Hz), ipso not observed, (d, J = 18.8 Hz), 55.3, 31.3 (t, J = 21.7 Hz), 29.4, 18.2; 31 P{ 1 H} Thiobenzamide 5 (4a) (synthesis with the use of f 8 -LR). NH 2 f 8 -LR THF 55 C NH 2 A chlenk tube was charged under N 2 atmosphere with the benzamide (3a) ( g, mmol), f 8 -Lawesson s reagent (f 8 -LR) (0.132 g, mmol), THF (4 ml), and stirred at 55 C. After 4 h, when the reaction was completed as determined by TLC, alumina (2 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml) to give 4a as a yellow solid ( g, mmol, 94%). 1 H and 13 C NMR spectral data matched a commercial sample. 6 NMR (CDCl 3 ): 1 H (m, 2H, C 6 H 5 ), (m, 3H, C 6 H 5 ); 13 C{ 1 H} 203.0, 139.3, 132.2, 128.6, Thiobenzamide 5 (4a) (synthesis with the use of f 6 -LR). NH 2 f 6 -LR THF 55 C NH 2 5 cheibye,.; Pedersen, B..; Lawesson,.-. Bull. oc. Chim. Belg. 1978, 87,

7 A chlenk tube was charged under N 2 atmosphere with the benzamide (3a) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.112 g, mmol), THF (4 ml), and placed into a 55 C oil bath. After 4 h, when the reaction was completed as determined by TLC, alumina (2 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml) to give 4a as a yellow solid ( g, mmol, 92%). 1 H and 13 C NMR spectral data matched a commercial sample. 6 Thioacetanilide 5 (4b). N H f 6 -LR THF 55 C N H A chlenk tube was charged under N 2 atmosphere with the acetanilide (3b) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.112 g, mmol), THF (4 ml), and placed into a 55 C oil bath. After 6 h, when the reaction was completed as determined by TLC, alumina (2 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml) to give 4b as a yellow solid ( g, mmol, 97%). 1 H and 13 C NMR spectral data matched a commercial sample. 7 NMR (CDCl 3 ): 1 H 9.81 (br s, 1H, NH), 8.97 (br s, 1.2H, NH), (m, 1.3H, C 6 H 5 ), (m, 3.0H, C 6 H 5 ), (m, 1.9H, C 6 H 5 ), 2.73 (s, 2.6H, CH 3 ), 2.51 (s, 2.0H, CH 3 ); 13 C{ 1 H} 204.7, 200.6, 138.7, 138.1, 129.7, 129.0, 128.1, 127.1, 125.2, 124.0, 36.2, Methyl-5-phenylthiophene 8 (6a). f 6 -LR THF 55 C A chlenk tube was charged under N 2 atmosphere with the 1-phenyl-1,4-pentanedione (5a) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.225 g, mmol), THF (4 ml), and placed into a 55 C oil bath. After 4 h, when the reaction was completed as determined by TLC, Liu, W.-D.; Chi, C.-C.; Pai, I-F.; Wu, A.-T.; Chung, W.-. J. rg. Chem. 2002, 67,

8 alumina (2 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml) to give 6a as a white solid ( g, mmol, 88%). 1 H and 13 C NMR spectral data matched those reported. 8 NMR (CDCl 3 ): 1 H 7.54 (d, J = 7.2 Hz, 2H, C 6 H 5 ), 7.34 (t, J = 7.2 Hz, 2H, C 6 H 5 ); (m, 1H, C 6 H 5 ), 7.09 (d, J = 3.3 Hz, 1H, C 4 H 2 ), 6.71 (d, J = 3.3 Hz, 1H, C 4 H 2 ), 2.50 (3H, s); 13 C{ 1 H} 142.1, 139.6, 134.8, 128.9, 127.1, 126.3, 125.6, 123.0, ,5-Diphenylthiophene 9 (6b). f 6 -LR THF 55 C A chlenk tube was charged under N 2 atmosphere with 1,2-dibenzoylethane (5b) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.112 g, mmol), THF (4 ml), and placed into a 55 C oil bath. After 6 h, when the reaction was completed as determined by TLC, alumina (2 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml) to give 6b as a white solid ( g, mmol, 92%). 1 H and 13 C NMR spectral data matched those reported. 8 NMR (CDCl 3 ): 1 H and (2m, 12H, 2C 6 H 5 and C 4 H 2 ); 13 C{ 1 H} 145.1, 135.7, 130.4, 129.0, 127.1, Butyl-4-methyl-2-phenyl-1,3-thiazole (8a). HN (CH 2 ) 3 CH 3 f 6 -LR THF 55 C N (CH 2 ) 3 CH 3 A chlenk tube was charged under N 2 atmosphere with N-(1-methyl-2-oxohexyl)benzamide 1 (7a) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.675 g, mmol), THF (16 ml), and placed into a 55 C oil bath. After 6 h, when the reaction was completed as determined by TLC, alumina (4 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile 9 Kiryanov, A. A.; ampson, P.; eed, A. J. J. rg. Chem. 2001, 66,

9 (30 ml). olvent was evaporated and the residue was purified by silica gel column chromatography (2 22 cm, hexanes/ethyl acetate 8:2) to give 8a (R f = 0.7) as a white solid ( g, mmol, 48%). econd fraction (R f = 0.6) was assigned as an analogous oxazole based upon GC/M ( g, mmol, 5%). Data for 8a: M (EI, 70 ev) m/z (rel intensity) 231 (M +, 100), 188 ([M-C 3 H 7 ] +, 100), 121 (PhC +, 15), 104 (PhCNH +, 27). HRM (EI, 70 ev) calcd. for (C 14 H 17 N): , found: IR (KBr) 2957, 2930, 2872, 2858, 1542, 1502, 1461, 1439, 1378, 1245, 1002, 994, 761, 720, 690 cm -1. NMR (CDCl 3 ): 1 H (m, 2H, C 6 H 5 ), (m, 3H, C 6 H 5 ); 2.75 (t, J = 7.4 Hz, 2H, C 3 HNCH 2 CH 2 ), 2.40 (s, 3H, CH 3 ), 1.64 (p, J = 7.4 Hz, 2H, C 3 HNCH 2 CH 2 ), 1.40 (hex, J = 7.4 Hz, 2H, CH 2 CH 2 CH 3 ), 0.95 (t, J = 7.4 Hz, 2H, CH 2 CH 3 ); 13 C{ 1 H} 163.6, 148.7, 134.1, 132.9, 129.4, 128.9,126.2, 33.9, 26.3, 22.3, 15.1, (4-Methoxyphenyl)-2-p-tolylthiazole 10 (8b). HN Me f 6 -LR MW N Me A chlenk tube was charged under N 2 atmosphere with N-[2-(4-methoxyphenyl)-2-oxoethyl]-4- methylbenzamide (7b) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.122 g, 0.10 mmol), and placed into an alumina bath inside the microwave oven. After 3 1 min full power (1200 W) irradiation alumina (2 g) was added and mixed thoroughly with spatula. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml). olvent was removed from the filtrate by rotary evaporation and the residue was recrystallized from methanol (1 ml) to give 8b as a white solid ( g, mmol, 82%). NMR (CDCl 3 ): 1 H 7.89 (s, 1H, C 3 NH), 7.84 (d, J = 8.2 Hz, 2H, C 6 H 4 ), 7.53 (d, J = 8.2 Hz, 2H, C 6 H 4 ), 7.25 (d, J = 8.2 Hz, 2H, C 6 H 4 ), 6.94 (d, J = 8.2 Hz, 2H, C 6 H 4 ), 3.85 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ); 13 C{ 1 H} 166.6, 159.8, 140.2, 138.8, 138.2, 131.3, 129.8, 128.1, 126.3, 124.2, 114.6, 55.5, Dölling, K.; Zaschke, H.; chubert, H. J. Prakt. Chem. 1979, 321,

10 2-Methyl-5-phenyl-1,3,4-thiadiazole 11 (10a). HN NH f 6 -LR THF 55 C N N A chlenk tube was charged under N 2 atmosphere with N'-acetylbenzohydrazide (9a) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.225 g, mmol), THF (4 ml), and placed into a 55 C oil bath. After 6 h, when the reaction was completed as determined by TLC, alumina (2 g) was added and the solvent was removed by rotary evaporation. The resulting solid was placed on a column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml). olvent was removed by rotary evaporation to give 10a as a white solid ( g, mmol, 94%). NMR (CDCl 3 ): 1 H (m, 2H, C 6 H 5 ), (m, 3H, C 6 H 5 ), 2.60 (s, 3H, CH 3 ); 13 C{ 1 H} 165.0, 163.7, 131.6, 129.1, 126.8, 124.0, ,5-Bis(4-methylphenyl)-1,3,4-thiadiazole 12 (10b). HN NH f 6 -LR THF 55 C N N A chlenk tube was charged under N 2 atmosphere with the 4-methyl-N'-(4- methylbenzoyl)benzohydrazine (9b) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.225 g, mmol), THF (4 ml), and placed into a 55 C oil bath. After 6 h, when the reaction was completed as determined by TLC, alumina (2 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml) to give 10b as a white solid ( g, mmol, 93%). NMR (CDCl 3 ): 1 H 7.91 (d, J = 8.2 Hz, 4H, C 6 H 5 ), 7.31 (d, J = 8.1 Hz, 4H, C 6 H 5 ), 2.44 (s, 6H, CH 3 ); 13 C{ 1 H} 168.0, 141.6, 129.9, 127.9, 127.6, (a) Ikeda, N.; Yada, A.; Takase, K. Yakugaku Zasshi 1970, 90, 95-98; Chem. Abstr. 1970, 72, 90374p. (b) Moss,. F.; Taylor, D. R. J. Chem. oc., Perkin Trans , (c) Demchuk, D. V.; Lutsenko, A. I.; Troyanskii, E. I.; Nikishin, G. I. Izv. Akad. Nauk R er. Khim. 1989, ; Bull. Acad. ci. UR Div. Chem. ci. 1989, 38, kuma, K.; Nagakura, K.; Nakajima, Y.; Kubo, K.; hioji, K. ynthesis 2004,

11 2',3',5'-Tri--acetyl-4-thiouridine 13 (12a). HN N Ac Ac Ac f 6 -LR THF 50 C Ac = CH 3 C HN N Ac Ac Ac A chlenk tube was charged under N 2 atmosphere with 2',3',5'-tri--acetyl-uridine 11a ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.225 g, mmol), THF (4 ml), and placed into a 55 C oil bath. The reaction, monitored by TLC, was completed after 17 h. Alumina (2 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml) to give 12a as a yellow solid ( g, mmol, 94%). NMR (CDCl 3 ): 1 H (brs, 1H, NH), 7.27 (d, J = 7.6 Hz, 1H, H-6), 6.44 (d, J = 7.6 Hz, 1H, H-5), 5.99 (d, J = 4.6 Hz, 1H, H-1'), (m, 2H, H-2', H-3'), (m, 3H, H-4', H-5'), 2.14, 2.13, and 2.12 (3s, 9H, 3CH 3 C); 13 C{ 1 H} (C-4), (CH 3 C), (2CH 3 C), (C-2), (C-6), (C-5), 88.2 (C-1'), 80.1 (C-2'), 73.0 (C-4'), 70.0 (C- 3'), 63.1 (C-5'), 20.8 (CH 3 C), 20.5 (2CH 3 C). 3',5'-Di--acetyl-5-iodo-4-thio-2'-deoxyuridine 14 (12b). HN I HN I Ac Ac N f 6 -LR dioxane 100 C Ac = CH 3 C Ac Ac N A chlenk tube was charged under N 2 atmosphere with 3',5'-di--acetyl-5-iodo-2'-deoxyuridine (11b) ( g, mmol), f 6 -Lawesson s reagent (f 6 -LR) (0.112 g, mmol) and 13 ung, W. L. J. Chem. oc., Chem. Commun. 1982, Brancale, A.; McGuigan, C.; Algain, B.; avy, P.; Benhida, R.; Fourrey, J.-L.; Andrei, G.; noeck, R.; De Clercq, E.; Balzarini, J. Bioorg. Med. Chem. Lett. 2001, 11,

12 anhydrous dioxane (4 ml) and placed into a 100 C oil bath. The reaction, monitored by TLC, was completed after 4 h. Alumina (2 g) was added and the solvent was evaporated. The resulting solid was placed on a short column packed with FRP silica (2 g). The column was eluted with acetonitrile (20 ml). olvent was removed, and the residue was purified by silica gel column chromatography (hexanes/ethyl acetate 8:2) to give 12b as a yellow solid ( g, mmol, 56%). NMR (CDCl 3 ): 1 H (brs, 1H, NH), 8.05 (s, 1H, H-6), 6.24 (dd, J = 8.0, 5.8 Hz, 1H, H-1 ), 5.23 (dt, J = 6.4, 2.0 Hz, 2H, H-3'), 4.37 (m, 3H, H-4' and H-5'), 2.62 and 2.55 (2dd, J = 5.8, 2.0 Hz, 2H, H-2'), 2.20 (s, 3H CH 3 ), 2.11 (s, 3H, CH 3 ); 13 C{ 1 H} (C-4), (CCH 3 ), (CCH 3 ), (C-2), (C-6), 86.0 (C-1'), 83.1 (C-4'), 82.9 (C-5), 74.2 (C-3'), 63.9 (C-5'), 38.6 (C-2'), 21.3 (CCH 3 ), 21.0 (CCH 3 ). 12

13 13 C NMR spectrum for 1-f 6 (CDCl 3 ) NAME Zoltan-upp EXPN 38 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 1024 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC (CF 2 ) 5 CF ppm 13

14 1 H NMR spectrum for 1-f 6 (CDCl 3 ) ppm NAME Zoltan-upp EXPN 37 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC (CF 2 ) 5 CF 3 14

15 13 C NMR spectrum for 1-f 8 (CDCl 3 ) NAME Zoltan-upp EXPN 91 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 2048 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC (CF 2 ) 7 CF ppm 15

16 1 H NMR spectrum for 1-f 8 (CDCl 3 ) ppm NAME Zoltan-upp EXPN 90 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC (CF 2 ) 7 CF 3 16

17 13 C NMR spectrum for f 6 -LR (THF-d 8 ) NAME Zoltan-upp EXPN 158 PRCN 1 Date_ Time 9.37 INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT THF N D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 1.00 Hz PC CF 3 (CF 2 ) 5 P P (CF2)5CF ppm 17

18 1 H NMR spectrum for f 6 -LR (THF-d 8 ) ppm NAME Nick EXPN 135 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT THF N 16 D 2 WH Hz FIDRE Hz AQ sec RG 362 DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC CF 3 (CF 2 ) 5 P P (CF2)5CF3 18

19 M for f 6 -LR (CF 2 ) 5 CF 3 P P CF 3 (CF 2 ) 5 19

20 13 C NMR spectrum for f 8 -LR (THF-d 8 ) NAME Nick EXPN 159 PRCN 1 Date_ Time 5.29 INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT THF D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 1.00 Hz PC CF 3 (CF 2 ) 7 P P (CF2)7CF ppm 20

21 M for f 8 -LR (CF 2 ) 7 CF 3 CF 3 (CF 2 ) 7 P P 21

22 13 C NMR spectrum for 4a (CDCl 3 ) thiobenzamide NAME Zoltan-upp EXPN 29 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 1024 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC NH ppm 22

23 13 C NMR spectrum for 4b (CDCl 3 ) thioacetanilide NAME Zoltan-upp EXPN 32 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 1024 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC N H ppm 23

24 1 H NMR spectrum for 4b (CDCl 3 ) thioacetanilide NAME Zoltan-upp EXPN 31 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC N H ppm

25 13 C NMR spectrum for 6a (CDCl 3 ) 2-methyl-5-phenylthiophene NAME Zoltan-upp EXPN 109 PRCN 1 Date_ Time 8.03 INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 8192 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC ppm 25

26 1 H NMR spectrum for 6a (CDCl 3 ) 2-methyl-5-phenylthiophene NAME Zoltan-upp EXPN 108 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG 362 DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC ppm

27 13 C NMR spectrum for 6b (CDCl 3 ) 2,5-diphenylthiophene NAME Zoltan-upp EXPN 62 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 700 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC ppm 27

28 1 H NMR spectrum for 6b (CDCl 3 ) 2,5-diphenylthiophene NAME Zoltan-upp EXPN 61 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC ppm

29 13 C NMR spectrum for 8a (CDCl 3 ) 5-butyl-4-methyl-2-phenyl-1,3-thiazole NAME Zoltan-upp EXPN 98 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 2048 D 4 WH Hz FIDRE Hz AQ sec RG DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC n-bu N ppm 29

30 1 H NMR spectrum for 8a (CDCl 3 ) 5-butyl-4-methyl-2-phenyl-1,3-thiazole NAME Zoltan-upp EXPN 97 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC n-bu N ppm

31 13 C NMR spectrum for 8b (CDCl 3 ) 5-(4-methoxyphenyl)-2-p-tolylthiazole NAME Zoltan-upp EXPN 1 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 3500 D 4 WH Hz FIDRE Hz AQ sec RG 71.8 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC Me N ppm 31

32 1 H NMR spectrum for 8b (CDCl 3 ) 5-(4-methoxyphenyl)-2-p-tolylthiazole NAME Zoltan-upp EXPN 2 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG 512 DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC Me N ppm

33 13 C NMR spectrum for 10a (CDCl 3 ) 2-methyl-5-phenyl-1,3,4-thiadiazole NAME Zoltan-upp EXPN 50 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 2048 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC N N ppm 33

34 1 H NMR spectrum for 10a (CDCl 3 ) 2-methyl-5-phenyl-1,3,4-thiadiazole NAME Zoltan-upp EXPN 49 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC N N ppm

35 13 C NMR spectrum for 10b (CDCl 3 ) 2,5-bis-(4-methylphenyl)-1,3,4-thiadiazole NAME Zoltan-upp EXPN 47 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 2048 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC N N ppm 35

36 1 H NMR spectrum for 10b (CDCl 3 ) 2,5-bis-(4-methylphenyl)-1,3,4-thiadiazole NAME Zoltan-upp EXPN 46 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC N N ppm

37 13 C NMR spectrum for 12a (CDCl 3 ) 2',3',5'-tri--acetyl-4-thiouridine ppm NAME Zoltan-upp EXPN 22 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 286 D 4 WH Hz FIDRE Hz AQ sec RG 90.5 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC HN N Ac Ac Ac 37

38 1 H NMR spectrum for 12a (CDCl 3 ) 2',3',5'-tri--acetyl-4-thiouridine ppm NAME Zoltan-upp EXPN 21 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG 71.8 DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC HN N Ac Ac Ac 38

39 13 C NMR spectrum for 12b (CDCl 3 ) 3',5'-di--acetyl-5-iodo-4-thio-2'-deoxyuridine ppm NAME Zoltan-upp EXPN 69 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zgdc TD LVENT CDCl3 N 2048 D 4 WH Hz FIDRE Hz AQ sec RG 57 DW usec D sec d sec NUC1 13C P usec PL db F MHz ======== CHANNEL f2 ======== CPDPRG2 waltz16 NUC2 1H PCPD usec PL db PL db F MHz I F MHz B 0 LB 3.00 Hz PC HN I N Ac Ac 39

40 1 H NMR spectrum for 12b (CDCl 3 ) 3',5'-di--acetyl-5-iodo-4-thio-2'-deoxyuridine ppm NAME Zoltan-upp EXPN 68 PRCN 1 Date_ Time INTRUM spect PRBHD 5 mm Multinucl PULPRG zg TD 4096 LVENT CDCl3 N 16 D 2 WH Hz FIDRE Hz AQ sec RG DW usec D sec NUC1 1H P usec PL db F MHz I F MHz B 0 LB 0.03 Hz PC HN I N Ac Ac 40