Supplementary Information

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1 Supplementary Information Application of Ynamides in the Synthesis of 2- (Tosylamido)- and 2,5-Bis-(tosylamido)thiophenes Imen Talbi, #, Carole Alayrac,*,# Jean-François Lohier, # Soufiane Touil, and Bernhard Witulski*,# # Laboratoire de Chimie Moléculaire et Thioorganique, CNRS UMR 6507, Normandie Univ, ENSICAEN & UNICAEN, 6 bvd Maréchal Juin, Caen, France. Laboratory of Heteroatom Organic Chemistry, University of Carthage, Faculty of Sciences of Bizerte, Jarzouna, Tunisia. Content 1. Compilation of Current Approaches to Amino- and Amidothiophenes S-2 2. General Remarks S-3 3. Experimental Part S H and 13 C NMR spectra S-18 S1

2 1. Compilation of Current Approaches to Amino- and Amidothiophenes Fig. S1. Different routes towards 2-amino and 2-amidothiophenes References: (S1) (a) Watanabe, M.; Yamamoto, T.; Nishiyama, M. Chem. Commun. 2000, 133. (b) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2003, 68, (S2) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, (b) Lu, Z.; Twieg, R. J. Tetrahedron 2005, 61, 903. (c) Wang, S.; Ni, Z.; Huang, X.; Wang, J.; Pan, Y. Org. Lett. 2014, 16, (S3) (a) Prim, D.; Kirsch, G. Tetrahedron 1999, 55, (b) Sarkar, P.; Maiti, S.; Ghosh, K.; Sengupta (Bandyopadhyay), S.; Butcher, R. J.; Mukhopadhyay, C. Tetrahedron Lett. 2014, 55, 996. (S4) (a) Fabbro, C.; Armani, S.; Carloni, L.-E.; De Leo, F.; Wouters, J.; Bonifazi, D. Eur. J. Org. Chem. 2014, 5487 and citations therein. (b) Whittamore, P. R. O.; Addie, M. S.; Bennett, S. N. L.; Birch, A. M.; Butters, M.; Godfrey, L.; Kenny, P. W.; Morley, A. D.; Murray, P. M.; Oikonomakos, N. G. et al Bioorg. Med. Chem. Lett. 2006, 16, (S5) (a) Gewald, K. Angew. Chem. 1961, 73, 114. (b) For a recent review, see: Puterová, Z.; Krutošíková, A.; Végh, D. Arkivoc 2010, 209. (S6) (a) Tarasova, O. A.; Klyba, L. V.; Vvedensky, V. Yu.; Nedolya, N. A.; Trofimov, B. A.; Brandsma, L.; Verkruijsse, H. D. Eur. J. Org. Chem. 1998, 253. (b) Katritzky, A. R.; Wang, X.; Denisenko, A. J. Org. Chem. 2001, 66, (S7) (a) Luo, X.; Ge, L.-S.; An, X.-L.; Jin, J.-H.; Wang, Y.; Sun, P.-P.; Deng, W.-P. J. Org. Chem. 2015, 80, (b) Wen, L.-R.; He, T.; Lan, M.-C.; Li, M. J. Org. Chem. 2013, 78, (S8) (a) Rahaim, R. J., Jr.; Maleczka, R. E., Jr. Org. Lett. 2005, 7, (b) Klemm, L. H.; Hsin, W. J. Heterocyclic Chem. 1975, 12, (c) Nguyen, S. T.; Ding, X.; Peet, N. P. Synthesis 2013, 45, S2

3 2. General Remarks Chromatographic purifications were performed using Merck silica gel Si 60 (40-63 μm) and TLC were developed on silica gel 60-F254 plates (0.1 mm) with UV detection. 1 H and 13 C NMR spectra were recorded on a BRUKER AVANCE III 400 or 500 spectrometer. 1 H and 13 C NMR chemical shifts are given in ppm using the TMS signal (0 ppm) and the residual peak of chloroform-d (77.16 ppm) respectively as internal reference. For 1 H and 13 C NMR spectra measured in CD3CN, the chemical shifts are given using the solvent residual peak (1.94 and 1.32 ppm respectively) as internal reference. Coupling constants are reported in Hertz (Hz). Abbreviations are used as follows: s = singlet, d = doublet, t = triplet, m = multiplet. Infrared (IR) spectra were recorded on a Perkin Elmer Spectrum One spectrometer equipped with an ATR device and only the strongest or structurally most important peaks are listed. High Resolution Mass Spectrometry (HRMS) was performed with a QTOF Micro WATERS spectrometer (ESI). Elemental analyses were performed with a ThermoQuest NA 2500 CHNS-O device. Melting points (Mp) were measured with a melting point microscope or an electrothermal apparatus and are not corrected. X-Ray diffraction analysis was performed on a Bruker-Nonius Kappa CCD single-crystal diffractometer (MoKα radiation λ = Å; graphite monochromator). 3. Experimental Part General procedure for thiophenes 1a-c: To a solution of 3a-c (0.20 mmol) in a 1:1 mixture of EtOH and THF (2 ml) was added Na2S 9H2O (2 equiv.). The reaction mixture was stirred at 50 C until complete conversion (TLC monitoring). After cooling to rt the reaction mixture was treated with CH2Cl2 and brine. The aqueous layer was extracted 3 times with CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using pentane/etoac as eluent to afford 1a-c. Bis-(N-benzyl, N-(4-methylbenzenesulfonyl))thiophen-2,5-diamide (1a) Yield: 89% (47 mg) obtained from 3a (50 mg, 0.09 mmol) as a white solid. Mp C (CHCl3/Pentane). Rf = 0.45 (Pentane/EtOAc 8:2). 1 H NMR (400 MHz, CDCl3) 7.47 (d, 3 J S3

4 = 8.1 Hz, 4H), (m, 10H), (m, 4H), 6.32 (s, 2H), 4.54 (s, 4H), 2.45 (s, 6H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (2 CH), (CH), 56.4 (CH2), 21.8 (CH3). IR (ATR) 3033, 1597, 1553, 1495, 1456, 1348, 1162, 1090, 810, 701, 674 cm 1. HRMS (ESI) Calcd for C32H30N2O4NaS3 [M+Na] + : Found: Bis-(N-allyl, N-(4-methylbenzenesulfonyl))thiophen-2,5-diamide (1b) Yield: 69% (73 mg) obtained from 3b (100 mg, 0.21 mmol), white crystals with mp C (CHCl3/Pentane). Rf = 0.63 (Pentane/EtOAc 8:2). 1 H NMR (500 MHz, CDCl3) 7.52 (d, 3 J = 8.2 Hz, 4H), 7.26 (d, 3 J = 8.2 Hz, 4H), 6.58 (s, 2H), (m, 2H), (m, 4H), 4.08 (d, 3 J = 6.3 Hz, 4H), 2.44 (s, 6H). 13 C NMR (125 MHz, CDCl3) (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH2), 55.3 (CH2), 21.8 (CH3). IR (ATR) 2980, 1596, 1555, 1495, 1451, 1354, 1162, 1088, 815, 663 cm 1. HRMS (ESI) Calcd for C24H26N2O4NaS3 [M+Na] + : Found: Anal. Calcd for C24H26N2O4S3 (502.7): C, 57.35; H, 5.21; N, 5.57; S, Found: C, 57.19; H, 5.33; N, 5.34; S, Single crystals of 1b suitable for X-ray crystallographic analysis were obtained by slow diffusion of pentane into a CHCl3-solution. S4

5 X-ray diffraction experiments for monocrystal of 1b were performed at 150 K with graphite monochromatized Mo Kα radiation (λ = Å) on a Bruker Nonius Kappa CCD area detector diffractometer. Formula C24H26N2O4S3, formula weight , crystal system monoclinic, space group P21/c, a = (2) Å, b = (5) Å, c = (2) Å, β = (1), V = (9) Å 3, Z = 4, calculated density = g/cm 3, μ = mm 1, measured reflections, 5056 independent reflections, Rint = , R[F 2 >2σ(F 2 )] = , wr(f 2 ) = , GOF = 1.020, 2θmax = 52.78, 300 parameters, final difference map within and eå -3. Program(s) used to solve structure: SHELXS 97. Program(s) used to refine structure: SHELXL CCDC contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via Bis-(N-n-butyl, N-(4-methylbenzenesulfonyl))thiophen-2,5-diamide (1c) Yield: 92% (49 mg) obtained from 3c (50 mg, 0.10 mmol) as a white solid. Mp C (Heptane). Rf = 0.51 (Pentane/EtOAc 8:2). 1 H NMR (400 MHz, CDCl3) 7.51 (d, 3 J = 8.2 S5

6 Hz, 4H), 7.25 (d, 3 J = 8.2 Hz, 4H), 6.62 (s, 2H), 3.43 (t, 3 J = 7.0 Hz, 4H), 2.42 (s, 6H), (m, 8H), 0.90 (t, 3 J = 7.3 Hz, 6H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (CH), (CH), (CH), 52.2 (CH2), 30.3 (CH2), 21.7 (CH3), 19.7 (CH2), 13.7 (CH3). IR (ATR) 2960, 2932, 2867, 2168, 1598, 1557, 1457, 1352, 1187, 1164, 1088, 1045, 840, 810 cm 1. HRMS (ESI) Calcd for C26H34N2O4NaS3 [M+Na] + : Found: Bis-(N-phenyl, N-(4-methylbenzenesulfonyl))thiophen-2,5-diamide (1d) To a solution of 3d (130 mg, 0.24 mmol) in CH3CN (2.2 ml) was added Na2S 9H2O (176 mg, 0.73 mmol, 3 equiv.) and the reaction mixture was heated at 70 C for 50 min. After cooling to rt the reaction mixture was treated with CH2Cl2 and brine. The aqueous layer was extracted 3 times with CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using pentane/etoac 9:1 as eluent to give 1d in 62% yield (85 mg). Yellow solid. Mp C (CHCl3/Pentane). Rf = 0.22 (Pentane/EtOAc 8:2). 1 H NMR (400 MHz, CDCl3) 7.55 (d, 3 J = 8.2 Hz, 4H), (m, 14H), 6.59 (s, 2H), 2.45 (s, 6H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), 21.8 (CH3). IR (ATR) 2330, 2114, 1591, 1543, 1487, 1452, 1354, 1161, 1148, 1088, 953, 814, 699, 677 cm 1. HRMS (ESI) Calcd for C30H26N2O4NaS3 [M+Na] + : Found: General procedure for diynes 4: In a two-neck flask equipped with a reflux condenser were introduced under argon atmosphere CuI (3 mg, 5 mol%) and NH2OH HCl (7 mg, 30 mol%) in oxygen-free MeOH (3 ml). To the mixture was added n-bunh2 (51 mg, 69 ml, 0.70 mmol, 2 equiv.) followed by MeOH (2 ml) and ynamide 5 (0.35 mmol, 1 equiv). The resulting solution was heated to 40 C and solid bromoalkyne 6 (1.5 equiv) or a solution of 6 (1.5 equiv.) in oxygen-free MeOH (2 ml) was added slowly within 25 min. The reaction mixture was further heated at 40 C for 1 h. Then CH2Cl2 and brine were added, the layers separated, and the aqueous layer was extracted 3 times with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered through Celite and concentrated S6

7 under reduced pressure. The residue was purified by silica gel column chromatography using pentane/etoac as eluent. N-Benzyl-N-(4-(4-nitrophenyl)buta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4a) S9 Yield: 93% (223 mg) obtained from 5a (160 mg, 0.56 mmol) as a yellow solid. Mp C (CHCl3/Pentane). Rf = 0.47 (Pentane/EtOAc 80:20). 1 H NMR (400 MHz, CDCl3) 8.14 (d, 3 J = 9 Hz, 2H), 7.73 (d, 3 J = 8.2 Hz, 2H), 7.54 (d, 3 J = 9 Hz, 2H), (m, 7H), 4.56 (s, 2H), 2.43 (s, 3H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (CH), (CH), (Cq), (CH), (2 CH), (CH), (CH), 79.3 (Cq), 78.9 (Cq), 77.2 (Cq), 58.6 (Cq), 55.7 (CH2), 21.7 (CH3). N-Benzyl-N-(4-(4-cyanophenyl)buta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4b) Yield: 82% (189 mg) obtained from 5a (160 mg, 0.56 mmol) as colorless solid. Mp C (CHCl3/Pentane). Rf = 0.28 (Pentane/EtOAc 85:15). 1 H NMR (500 MHz, CDCl3) 7.75 (d, 3 J = 8.3 Hz, 2H), 7.57 (d, 3 J = 8.3 Hz, 2H), 7.49 (d, 3 J = 8.3 Hz, 2H), (m, 7H), 4.57 (s, 2H), 2.45 (s, 3H). 13 C NMR (125 MHz, CDCl3) (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (Cq), (Cq), (Cq), 79.6 (Cq), 78.1 (Cq), 76.8 (Cq), 58.7 (Cq), 55.8 (CH2), 21.8 (CH3). IR (ATR) 3088, 3062, 2943, 2356, 2218, 2155, 1599, 1497, 1454, 1422, 1399, 1366, 1323, 1308, 1189, 1163, 1085, 1059, 1028 cm 1. HRMS (ESI) Calcd for C25H18N2O2NaS [M+Na] + : Found: Anal. Calcd for C25H18N2O2S (410.5): C, 73.15; H, 4.42; N, 6.82; S, Found: C, 73.04; H, 4.39; N, 6.85; S, S9 Witulski, B.; Schweikert, T.; Schollmeyer, D.; Nemkovich, N. A. Chem. Commun. 2010, 46, S7

8 N-Benzyl-N-(4-phenylbuta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4c) Yield: 53% (72 mg) obtained from 5a (100 mg, 0.35 mmol) as pale yellow crystals. Mp C (CHCl3/Pentane). Rf = 0.38 (Pentane/EtOAc 95:5). 1 H NMR (400 MHz, CDCl3) 7.75 (d, 3 J = 8.3 Hz, 2H), (m, 2H), (m, 10H), 4.56 (s, 2H), 2.44 (s, 3H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (Cq), 81.4 (Cq), 74.4 (Cq), 73.6 (Cq), 58.9 (Cq), 55.8 (CH2), 21.8 (CH3). IR (ATR) 2228, 2155, 1595, 1491, 1388, 1365, 1166, 1089, 1050, 815, 734 cm 1. HRMS (ESI) Calcd for C24H19NO2NaS [M+Na] + : Found: Anal. Calcd for C24H19NO2S (385.5): C, 74.78; H, 4.97; N, 3.63; S, Found: C, 74.46; H, 5.28; N, 3.40; S, N-Benzyl-N-(4-(2-thienyl)buta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4d) Yield: 85% (140 mg) obtained from 5a (120 mg, 0.42 mmol) as yellow crystals. Mp C (CHCl3/Pentane). Rf = 0.29 (Pentane/EtOAc 9:1). 1 H NMR (500 MHz, CDCl3) 7.74 (d, 3 J = 8.3 Hz, 2H), (m, 9H), 6.96 (dd, 3 J = 5.1 Hz, 3 J = 3.7 Hz, 1H), 4.56 (s, 2H), 2.45 (s, 3H). 13 C NMR (125 MHz, CDCl3) (Cq), (Cq), (CH), (Cq), (CH), (CH), (2 CH), (CH), (CH), (CH), (Cq), 77.9 (Cq), 76.6 (Cq), 74.5 (Cq), 59.1 (Cq), 55.9 (CH2), 21.8 (CH3). IR (ATR) 3065, 2223, 2151, 1596, 1495, 1426, 1384, 1366, 1336, 1166, 1089, 1029, 811, 701 cm 1. HRMS (ESI) Calcd for C22H17NO2NaS2 [M+Na] + : Found: N-((5-Methyl-5-hydroxy)hexa-1,3-diyn-1-yl)-N-benzyl-4-methylbenzenesulfonamide (4e) S9 Yield: 97% (1.23 g) obtained from 5a (1 g, 3.5 mmol), as a colorless solid. Mp C (CHCl3/Pentane). Rf = 0.58 (Pentane/EtOAc 1:1). 1 H NMR (400 MHz, CDCl3) 7.71 (d, 3 J = 8.3 Hz, 2H), (m, 7H), 4.51 (s, 2H), 2.44 (s, 3H), 2.06 (s, 1H), 1.50 (s, 6H). 13 C S8

9 NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), 86.5 (Cq), 71.6 (Cq), 66.7 (Cq), 65.8 (Cq), 58.2 (Cq), 55.7 (CH2), 31.2 (CH3), 21.8 (CH3). N-Allyl-N-(4-phenylbuta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4f) S10 Yield: 52% (140 mg) obtained from 5b (190 mg, 0.8 mmol), as a yellow oil. Rf = 0.36 (Pentane/EtOAc 95:5). 1 H NMR (400 MHz, CDCl3) 7.82 (d, 3 J = 8.3 Hz, 2H), 7.46 (dd, 3 J = 7.5 Hz, 4 J = 1.4 Hz, 2H), 7.37 (d, 3 J = 8.2 Hz, 2H), (m, 3H), 5.73 (ddt, 3 J = 16.6 Hz, 3 J = 10.2 Hz, 3 J = 6.3 Hz, 1H), (m, 2H), 4.02 (d, 3 J = 6.3 Hz, 2H), 2.46 (s, 3H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (Cq), (CH2), 81.2 (Cq), 74.1 (Cq), 73.6 (Cq), 58.5 (Cq), 54.4 (CH2), 21.8 (CH3). N-((5-Methyl-5-hydroxy)hexa-1,3-diyn-1-yl)-N-phenyl-4-methylbenzenesulfonamide (4g) Yield: 92% (240 mg) obtained from 5c (200 mg, 0.74 mmol), white crystals with mp C (CHCl3/Pentane). Rf = 0.39 (Pentane/EtOAc 7:3). 1 H NMR (400 MHz, CDCl3) 7.58 (d, 3 J = 8.3 Hz, 2H), (m, 5H), (m, 2H), 2.45 (s, 3H), 2.04 (s, 1H), 1.54 (s, 6H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), 86.8 (Cq), 71.7 (Cq), 66.7 (Cq), 65.9 (Cq), 57.1 (Cq), 31.2 (CH3), 21.9 (CH3). IR (ATR) 3305, 2986, 2930, 2250, 2166, 1594, 1485, 1455, 1371, 1174, 1088, 685, 658 cm 1. HRMS (ESI) Calcd for C20H19NO3NaS [M+Na] + : Found: S10 Ide, M.; Ohashi, K.; Mihara, S.; Iwasawa, T. Tetrahedron Lett. 2014, 55, S9

10 N-(2-Iodophenyl)-N-((5-methyl-5-hydroxy)hexa-1,3-diyn-1-yl)-4- methylbenzenesulfon-amide (4h) Yield: 97% (209 mg) obtained from 5d (178 mg, 0.45 mmol). Colorless crystals with mp C (CHCl3/Pentane). Rf = 0.56 (Pentane/EtOAc 1:1). 1 H NMR (400 MHz, CDCl3) (m, 1H), 7.76 (d, 3 J = 8.3 Hz, 2H), 7.38 (d, 3 J = 8.3 Hz, 2H), (m, 1H), (m, 2H), 2.49 (s, 3H), 1.98 (s, 1H), 1.53 (s, 6H). 13 C NMR (100 MHz, CDCl3) (Cq), (CH), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), 98.9 (Cq), 87.4 (Cq), 70.6 (Cq), 66.8 (Cq), 65.9 (Cq), 58.1 (Cq), 31.2 (CH3), 21.9 (CH3). IR (ATR) 3386, 3065, 2982, 2932, 2248, 2166, 1720, 1709, 1596, 1492, 1463, 1439, 1376, 1174 cm 1. HRMS (ESI) Calcd for C20H18NO3NaSI [M+Na] + : Found: Anal. Calcd for C20H18INO3S (479.3): C, 50.11; H, 3.79; N, Found: C, 50.23; H, 3.55; N, Thiophenes 2a-e and 2g were prepared according to the general procedure described for 1ac. Thiophenes 2h and 2j were prepared according to the synthesis of 1d but at a reaction temperature of 50 C. N-Benzyl, N-(4-methylbenzenesulfonyl)-5-(4-nitrophenyl)thiophen-2-amide (2a) Yield: 47% (18 mg) obtained as a yellow solid from 4a (35 mg, 0.11 mmol). Mp C (decomp.). Rf = 0.50 (Pentane/EtOAc 8:2). 1 H NMR (500 MHz, CDCl3) δ 8.18 (d, 3 J = 8.8 Hz, 2H), 7.67 (d, 3 J = 8.2 Hz, 2H), 7.57 (d, 3 J = 8.8 Hz, 2H), 7.33 (d, 3 J = 8.2 Hz, 2H), (m, 5H), 7.14 (d, 3 J = 4.0 Hz, 1H), 6.68 (d, 3 J = 4.0 Hz, 1H), 4.75 (s, 2H), 2.46 (s, 3H). 13 C NMR (125 MHz, CDCl3 ) δ (Cq), (Cq), (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), 56.5 (CH2), 21.8 (CH3). IR (ATR) 3025, 2924, 1594, 1511, 1497, 1454, 1338, 1191, 1157, 1113, 1088, 1035, 1026, 845, 812 cm 1. HRMS (ESI) Calcd for C24H21N2O4S2 [MH] + : Found: S10

11 N-Benzyl, N-(4-methylbenzenesulfonyl)-5-(4-cyanophenyl)thiophen-2-amide (2b) Yield: 66% (58 mg) obtained as a white solid from 4b (81 mg, 0.20 mmol). Mp C (decomp.). Rf = 0.31 (Pentane/EtOAc 8:2). 1 H NMR (500 MHz, CDCl3) 7.66 (d, 3 J = 8.2 Hz, 2H), 7.60 (d, 3 J = 8.3 Hz, 2H), 7.52 (d, 3 J = 8.3 Hz, 2H), 7.32 (d, 3 J = 8.2 Hz, 2H), (m, 5H), 7.08 (d, 3 J = 4.0 Hz, 1H), 6.66 (d, 3 J = 4.0 Hz, 1H), 4.73 (s, 2H), 2.46 (s, 3H). 13 C NMR (125 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (Cq), (Cq), 56.5 (CH2), 21.8 (CH3). IR (ATR) 2232, 1605, 1507, 1455, 1350, 1190, 1162, 1090, 1025, 839, 808 cm 1. HRMS (ESI) Calcd for C25H20N2O2NaS2 [M+Na] + : Found: N-Benzyl, N-(4-methylbenzenesulfonyl)-5-phenylthiophen-2-amide (2c) Yield: 91% (99 mg) obtained as a white solid from 4c (100 mg, 0.26 mmol). Mp C. Rf = 0.46 (Pentane/EtOAc 8:2). 1 H NMR (400 MHz, CDCl3) 7.67 (d, 3 J = 8.2 Hz, 2H), 7.44 (d, 3 J = 7.6 Hz, 2H), (m, 10H), 6.96 (d, 3 J = 3.9 Hz, 1H), 6.62 (d, 3 J = 3.9 Hz, 1H), 4.72 (s, 2H), 2.45 (s, 3H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), 56.7 (CH2), 21.8 (CH3). IR (ATR) 2324, 2197, 2085, 1599, 1496, 1456, 1347, 1163, 754 cm 1. HRMS (ESI) Calcd for C24H21NO2NaS2 [M+Na] + : Found: Anal. Calcd for C24H21NO2S2 (419.6): C, 68.70; H, 5.04; N, 3.34; S, Found: C, 68.94; H, 5.02; N, 2.95; S, N-Benzyl, N-(4-methylbenzenesulfonyl)-5-(2-thienyl)thiophen-2-amide (2d) Yield: 67% (30 mg) obtained as a white solid from 4d (41 mg, 0.10 mmol). Mp C. Rf = 0.30 (Pentane/EtOAc 9:1). 1 H NMR (400 MHz, CDCl3) 7.67 (d, 3 J = 8.2 Hz, 2H), S11

12 (m, 7H), 7.17 (dd, 3 J = 5.1 Hz, 4 J = 1.0 Hz, 1H), 7.03 (dd, 3 J = 3.6 Hz, 4 J = 1.0 Hz, 1H), 6.96 (dd, 3 J = 5.1 Hz, 3 J = 3.6 Hz, 1H), 6.81 (d, 3 J = 3.9 Hz, 1H), 6.54 (d, 3 J = 3.9 Hz, 1H), 4.70 (s, 2H), 2.46 (s, 3H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (2 CH), (CH), (CH), (CH), (CH), (CH), 56.6 (CH2), 21.8 (CH3). IR (ATR) 3086, 1598, 1513, 1495, 1452, 1424, 1348, 1161, 1089, 811, 699 cm 1. HRMS (ESI) Calcd for C22H19NO2S3Na [M+Na] + : Found: N-Benzyl, amide (2e) N-(4-methylbenzenesulfonyl)-5-((1-methyl-1-hydroxy)ethyl)thiophen-2- Yield: 79% (86 mg) obtained from 4e (100 mg, 0.27 mmol). Pale yellow crystals with mp C (CHCl3/Pentane). Rf = 0.42 (Pentane/EtOAc 7:3). 1 H NMR (500 MHz, CD3CN) 7.64 (d, 3 J = 8.3 Hz, 2H), 7.40 (d, 3 J = 8.0 Hz, 2H), (m, 5H), 6.57 (d, 3 J = 3.9 Hz, 1H), 6.47 (d, 3 J = 3.9 Hz, 1H), 4.70 (s, 2H), 3.41 (s, 1H), 2.45 (s, 3H), 1.44 (s, 6H). 13 C NMR (125 MHz, CD3CN) (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (2 CH), (CH), (CH), 71.5 (Cq), 57.2 (CH2), 32.3 (CH3), 21.6 (CH3). IR (ATR) 1339, 1156, 828, 708 cm 1. HRMS (ESI) Calcd for C21H23NO3NaS2 [M+Na] + : Found: N-Benzyl, N-(4-methylbenzenesulfonyl)-5-(prop-1-en-2-yl)thiophen-2-amide (2f) To a 10-3 M solution of thiophene 2e (38 mg, 95 mol) in degazed CHCl3 (95 ml) were added 5 drops of 37% aq. HCl and the solution was stirred at rt for 1 h. The reaction mixture was cooled down to 0 C and Et3N (0.5 ml) was added dropwise. Then the reaction mixture was filtered on a pad of celite and the solvent was removed under vacuum. The residue was purified by silica gel column chromatography (pentane/etoac 9:1) to give 2f as a white solid (32 mg, 88% yield). Mp C (CHCl3/Pentane). Rf = 0.45 (Pentane/EtOAc 9:1). 1 H NMR (500 MHz, CDCl3) 7.65 (d, 3 J = 8.2 Hz, 2H), (m, 7H), 6.66 (d, 3 J = 3.9 Hz, 1H), 6.52 (d, 3 J S12

13 = 3.9 Hz, 1H), 5.19 (s, 1H), 4.87 (s, 1H), 4.68 (s, 2H), 2.45 (s, 3H), 2.02 (s, 3H). 13 C NMR (125 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH2), 56.5 (CH2), 21.8 (CH3), 21.2 (CH3). IR (ATR) 3064, 2923, 2854, 2229, 1666, 1619, 1599, 1537, 1495, 1451, 1348, 1162, 1090, 1026, 819, 810 cm 1. HRMS (ESI) Calcd for C21H21NO2NaS2 [M+Na] + : Found: N-Allyl, N-(4-methylbenzenesulfonyl)-5-phenylthiophen-2-amide (2g) Yield: 75% (41 mg) obtained from 4f (50 mg, 0.15 mmol) as pale yellow crystals. Mp C (CHCl3/Pentane). Rf = 0.5 (Pentane/EtOAc 9:1). 1 H NMR (500 MHz, CDCl3) 7.63 (d, 3 J = 8.3 Hz, 2H), (m, 2H), 7.35 (dd, 3 J = 7.8 Hz, 3 J = 7.4 Hz, 2H), (m, 3H), 7.06 (d, 3 J = 3.9 Hz, 1H), 6.74 (d, 3 J = 3.9 Hz, 1H), (m, 1H), (m, 2H), 4.19 (d, 3 J = 6.3 Hz, 2H), 2.43 (s, 3H). 13 C NMR (125 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH2), 55.5 (CH2), 21.7 (CH3). IR (ATR) 3063, 3026, 2923, 2857, 1597, 1548, 1497, 1446, 1350, 1163, 1089, 811, 755 cm 1. HRMS (ESI) Calcd for C20H19NO2NaS2 [M+Na] + : Found: S13

14 Single crystals of 2g suitable for X-ray crystallographic analysis were obtained by slow diffusion of pentane into a CHCl3-solution. X-ray diffraction experiments for monocrystal of 2g were performed at 150 K with graphite monochromatized Mo Kα radiation (λ = Å) on a Bruker Nonius Kappa CCD area detector diffractometer. Formula C20H19NO2S2, formula weight , crystal system monoclinic, space group P21, a = (3) Å, b = (2) Å, c = (5) Å, β = (14), V = (5) Å 3, Z = 2, calculated density = g/cm 3, μ = mm 1, measured reflections, 5655 independent reflections, Rint = , R[F 2 >2σ(F 2 )] = , wr(f 2 ) = , GOF = 1.057, 2θmax = 60.32, 227 parameters, final difference map within and eå -3. Program(s) used to solve structure: SHELXS 97. Program(s) used to refine structure: SHELXL CCDC contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via 5-(1-Methyl-1-hydroxy)ethyl-N-phenyl, amide (2h) N-(4-methylbenzenesulfonyl)thiophen-2- Yield: 63% (68 mg) obtained from 4g (100 mg, 0.28 mmol) as a yellow solid. Mp C (decomp.). Rf = 0.31 (Pentane/EtOAc 7:3). 1 H NMR (500 MHz, CD3CN) 7.59 (d, 3 J = 8.3 Hz, 2H), (m, 5H), (m, 2H), 6.73 (d, 3 J = 3.9 Hz, 1H), 6.68 (d, 3 J = 3.9 Hz, 1H), 3.51 (s, 1H), 2.44 (s, 3H), 1.49 (s, 6H). 13 C NMR (125 MHz, CD3CN) (Cq), S14

15 145.8 (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), 71.6 (Cq), 32.3 (CH3), 21.6 (CH3). IR (ATR) 3200, 2980, 2925, 2854, 1598, 1495, 1487, 1452, 1355, 1164, 1155, 1089, 957, 940, 810 cm 1. HRMS (ESI) Calcd for C20H21NO3NaS2 [M+Na] + : Found: N-(4-Methylbenzenesulfonyl)-N-phenyl-5-(prop-1-en-2-yl)thiophen-2-amide (2i) Following the same procedure described for 2f. Yield: 86% (5.4 mg) obtained from 2h (6.6 mg, 17 mol) as a white solid. Mp C. Rf = 0.49 (Pentane/EtOAc 9:1). 1 H NMR (400 MHz, CDCl3) 7.62 (d, 3 J = 8.3 Hz, 2H), (m, 7H), 6.75 and 6.73 (AB, JAB = 3.9 Hz, 2H), 5.25 (s, 1H), 4.90 (s, 1H), 2.45 (s, 3H), 2.06 (s, 3H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (2 CH), (CH), (CH), (CH2), 21.8 (CH3), 21.2 (CH3). IR (ATR) 2931, 2860, 1598, 1557, 1484, 1449, 1354, 1186, 1163, 1088, 1044, 814 cm 1. HRMS (ESI) Calcd for C20H19NO2NaS2 [M+Na] + : Found: N-(2-Iodophenyl), N-(4-methylbenzenesulfonyl)-5-(1-methyl-1-hydroxy)ethylthiophen-2-amide (2j) Yield: 51% (52 mg) obtained from 4h (100 mg, 0.20 mmol) as a yellow solid. Mp C. Rf = 0.3 (Pentane/EtOAc 6:4). 1 H NMR (500 MHz, CD3CN) 7.99 (dd, 3 J = 7.9 Hz, 4 J = 1.4 Hz, 1H), 7.61 (d, 3 J = 8.3 Hz, 2H), (m, 3H), 7.23 (dd, 3 J = 7.9 Hz, 4 J = 1.5 Hz, 1H), (m, 1H), 6.81 (d, 3 J = 3.8 Hz, 1H), 6.67 (d, 3 J = 3.8 Hz, 1H), 3.48 (s, 1H), 2.46 (s, 3H), 1.48 (s, 6H). 13 C NMR (125 MHz, CD3CN) (Cq), (Cq), (Cq), (CH), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (Cq), 71.7 (Cq), 32.3 (CH3), 21.7 (CH3). IR (ATR) 2980, 1594, 1544, 1487, 1459, 1351, 1151, 1087, 941, 815 cm 1. HRMS (ESI) Calcd for C20H20NO3NaS2I [M+Na] + : Found: S15

16 S16

17 N-(2-Iodophenyl), (2k) N-(4-methylbenzenesulfonyl)-5-(prop-1-en-2-yl)thiophen-2-amide Following the same procedure described for 2f. Yield: 79% (15 mg) obtained from 2j (20 mg, 39 mol) as a white solid. Mp C (CHCl3/Pentane). Rf = 0.30 (Pentane/EtOAc 9:1). 1 H NMR (500 MHz, CDCl3) 7.93 (dd, 3 J = 7.9 Hz, 4 J = 1.1 Hz, 1H), 7.68 (d, 3 J = 8.2 Hz, 2H), (m, 3H), 7.17 (dd, 3 J = 7.8 Hz, 4 J = 1.3 Hz, 1H), (m, 1H), 6.90 (d, 3 J = 3.9 Hz, 1H), 6.76 (d, 3 J = 3.9 Hz, 1H), 5.25 (s, 1H), 4.90 (s, 1H), 2.46 (s, 3H), 2.06 (s, 3H). 13 C NMR (125 MHz, CDCl3) (Cq), (Cq), (Cq), (CH), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH2), (Cq), 21.8 (CH3), 21.3 (CH3). IR (ATR) 2924, 2215, 1595, 1494, 1459, 1358, 1169, 1156, 1087, 800 cm 1. HRMS (ESI) Calcd for C20H18NO2NaS2I [M+Na] + : Found: ,5-Bis-(N-benzyl, N-(4-methylbenzenesulfonyl)buta-1,3-diyn-4-yl)thiophenediamide (8) In a 3-neck flask equipped with an addition funnel were introduced under argon atmosphere CuI (20 mg, 5 mol%) and NH2OH HCl (42 mg, 30 mol%) in oxygen-free MeOH (17 ml). To the mixture was added n-bunh2 (0.4 ml, 2 equiv.) followed by MeOH (2 ml), ynamide 5a (571 mg, 2 mmol, 1 equiv.) as a solid and dry THF (10 ml). To the resulting yellow solution was added dropwise within 25 min a solution of bis-bromoacetylenic thiophene 7 (238 mg, 0.82 mmol, 0.41 equiv.) in MeOH/THF 5:1 (9.6 ml). The reaction mixture was then stirred at rt for 1 h. Then CH2Cl2 and brine were added, the layers separated, and the aqueous layer was extracted 3 times with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using pentane/etoac 8:2 then 7:3 as eluent to give 8 in 52% yield (300 mg). S17

18 Yellow-orange solid. Mp C (decomp.). Rf = 0.50 (Pentane/EtOAc 7:3). 1 H NMR (400 MHz, CDCl3) 7.73 (d, 3 J = 8.0 Hz, 4H), (m, 14H), 7.06 (s, 2H), 4.56 (s, 4H), 2.44 (s, 6H). 13 C NMR (100 MHz, CDCl3) (Cq), (Cq), (CH), (Cq), (CH), (CH), (CH), (CH), (CH), (Cq), 79.2 (Cq), 77.6 (Cq), 73.8 (Cq), 59.0 (Cq), 55.8 (CH2), 21.8 (CH3). IR (ATR) 3032, 2925, 2214, 2148, 1596, 1520, 1495, 1455, 1366, 1208, 1187, 1166, 1087, 1003, 808 cm 1. HRMS (ESI) Calcd for C40H30N2O4NaS3 [M+Na] + : Found: Bis-(N-benzyl, N-(4-methylbenzenesulfonyl))terthiophenediamide (9) To a solution of 8 (75 mg, 0.11 mmol) in a 1:1 mixture of EtOH and THF (2 ml) was added Na2S 9H2O (105 mg, 0.43 mmol, 4 equiv.). The reaction mixture was stirred at 50 C during 1.5 h. After cooling to rt the reaction mixture was treated with CH2Cl2 and brine. The aqueous layer was extracted 3 times with CH2Cl2 and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using pentane/etoac 7:3 as eluent to afford 9 (19 mg, 23% yield). Yellow solid (CHCl3/Pentane) with mp 230 C (decomp.). Rf = 0.46 (Pentane/EtOAc 7:3). 1 H NMR (500 MHz, CDCl3) 7.66 (d, 3 J = 8.2 Hz, 4H), (m, 14H), 6.88 (s, 2H), 6.77 (d, 3 J = 3.9 Hz, 2H), 6.53 (d, 3 J = 3.9 Hz, 2H), 4.69 (s, 4H), 2.46 (s, 6H). 13 C NMR (125 MHz, CDCl3) (Cq), (Cq), (Cq), (Cq), (Cq), (Cq), (CH), (CH), (CH), (CH), (CH), (CH), (CH), (CH), 56.6 (CH2), 21.8 (CH3). IR (ATR) 2921, 2852, 1597, 1517, 1495, 1455, 1349, 1162, 1088, 1017, 811, 786 cm 1. HRMS (ESI) Calcd for C40H34N2O4NaS5 [M+Na] + : Found: S18

19 H2O 4. 1 H and 13 C NMR Spectra Bis-(N-benzyl, N-(4-methylbenzenesulfonyl))thiophen-2,5-diamide (1a) 1 H NMR (400 MHz, CDCl3) of 1a 13 C NMR (100 MHz, CDCl3) of 1a S19

20 Bis-(N-allyl, N-(4-methylbenzenesulfonyl))thiophen-2,5-diamide (1b) 1 H NMR (500 MHz, CDCl3) of 1b 13 C NMR (125 MHz, CDCl3) of 1b S20

21 Bis-(N-n-butyl, N-(4-methylbenzenesulfonyl))thiophen-2,5-diamide (1c) 1 H NMR (400 MHz, CDCl3) of 1c 13 C NMR (100 MHz, CDCl3) of 1c S21

22 H2O Bis-(N-phenyl, N-(4-methylbenzenesulfonyl))thiophen-2,5-diamide (1d) CH2Cl2 * * 1 H NMR (400 MHz, CDCl3) of 1d (* traces of residual pentane, = 1.27, 0.88) 13 C NMR (100 MHz, CDCl3) of 1d S22

23 N-Benzyl-N-(4-(4-cyanophenyl)buta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4b) 1 H NMR (500 MHz, CDCl3) of 4b 13 C NMR (125 MHz, CDCl3) of 4b S23

24 H2O N-Benzyl-N-(4-phenylbuta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4c) 1 H NMR (400 MHz, CDCl3) of 4c 13 C NMR (100 MHz, CDCl3) of 4c S24

25 H2O N-Benzyl-N-(4-(2-thienyl)buta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4d) 1 H NMR (500 MHz, CDCl3) of 4d 13 C NMR (125 MHz, CDCl3) of 4d S25

26 N-((5-Methyl-5-hydroxy)hexa-1,3-diyn-1-yl)-N-benzyl-4-methylbenzenesulfonamide (4e) 1 H NMR (400 MHz, CDCl3) of 4e 13 C NMR (100 MHz, CDCl3) of 4e S26

27 N-Allyl-N-(4-phenylbuta-1,3-diyn-1-yl)-4-methylbenzenesulfonamide (4f) 1 H NMR (400 MHz, CDCl3) of 4f 13 C NMR (100 MHz, CDCl3) of 4f S27

28 N-((5-Methyl-5-hydroxy)hexa-1,3-diyn-1-yl)-N-phenyl-4-methylbenzenesulfonamide (4g) 1 H NMR (400 MHz, CDCl3) of 4g 13 C NMR (100 MHz, CDCl3) of 4g S28

29 N-(2-Iodophenyl)-N-((5-methyl-5-hydroxy)hexa-1,3-diyn-1-yl)-4- methylbenzenesulfonamide (4h) 1 H NMR (400 MHz, CDCl3) of 4h 13 C NMR (100 MHz, CDCl3) of 4h S29

30 H2O N-Benzyl, N-(4-methylbenzenesulfonyl)-5-(4-nitrophenyl)thiophen-2-amide (2a) 1 H NMR (500 MHz, CDCl3) of 2a 13 C NMR (125 MHz, CDCl3) of 2a S30

31 H2O N-Benzyl, N-(4-methylbenzenesulfonyl)-5-(4-cyanophenyl)thiophen-2-amide (2b) 1 H NMR (500 MHz, CDCl3) of 2b 13 C NMR (125 MHz, CDCl3) of 2b S31

32 H2O N-Benzyl, N-(4-methylbenzenesulfonyl)-5-phenylthiophen-2-amide (2c) 1 H NMR (400 MHz, CDCl3) of 2c 13 C NMR (100 MHz, CDCl3) of 2c S32

33 H2O N-Benzyl, N-(4-methylbenzenesulfonyl)-5-(2-thienyl)thiophen-2-amide (2d) 1 H NMR (400 MHz, CDCl3) of 2d 13 C NMR (100 MHz, CDCl3) of 2d S33

34 H2O N-Benzyl, N-(4-methylbenzenesulfonyl)-5-((1-methyl-1-hydroxy)ethyl)thiophen-2- amide (2e) * 1 H NMR (500 MHz, CD3CN) of 2e (* CD3CN solvent residual signal at = 1.94) * * 13 C NMR (125 MHz, CD3CN) of 2e (* CD3CN solvent residual signals at = 118.3, 1.32) S34

35 Spontaneous evolution of 2e into 2f in CDCl3 monitored by 1 H NMR (400MHz) (a) 1 H NMR (400 MHz, CDCl3) spectrum of 2e (top). (b) 1 H NMR (400 MHz, CDCl3) analysis showing peaks related to 2e and 2f (middle). (c) 1 H NMR analysis repeated after 15 days showing that the peaks related to 2e have disappeared (bottom). S35

36 H2O N-Benzyl, N-(4-methylbenzenesulfonyl)-5-(prop-1-en-2-yl)thiophen-2-amide (2f) 1 H NMR (500 MHz, CDCl3) of 2f 13 C NMR (125 MHz, CDCl3) of 2f S36

37 H2O N-Allyl, N-(4-methylbenzenesulfonyl)-5-phenylthiophen-2-amide (2g) 1 H NMR (500 MHz, CDCl3) of 2g 13 C NMR (125 MHz, CDCl3) of 2g S37

38 H2O 5-(1-Methyl-1-hydroxy)ethyl-(N-phenyl, N-4-methyl-benzenesulfonyl)thiophen-2- amide (2h) CH2Cl2 * 1 H NMR (500 MHz, CD3CN) of 2h (* CD3CN solvent residual signal at = 1.94) * * 13 C NMR (125 MHz, CD3CN) of 2h (* CD3CN solvent residual signals at = 118.3, 1.32) S38

39 N-(4-Methylbenzenesulfonyl)-N-phenyl-5-(prop-1-en-2-yl)thiophen-2-amide (2i) CH2Cl2 H2O 1 H NMR (400 MHz, CDCl3) of 2i 13 C NMR (100 MHz, CDCl3) of 2i S39

40 N-(2-Iodophenyl), N-(4-methylbenzenesulfonyl)-5-(1-methyl-1-hydroxy)ethylthiophen-2-amide (2j) * 1 H NMR (500 MHz, CD3CN) of 2j (* CD3CN solvent residual signal = 1.94). * * 13 C NMR (125 MHz, CD3CN) of 2j (* CD3CN solvent residual signals at = 118.3, 1.32). S40

41 H2O N-(2-Iodophenyl), N-(4-methylbenzenesulfonyl)-5-(prop-1-en-2-yl)thiophen-2-amide (2k) * * 1 H NMR (500 MHz, CDCl3) of 2k (* traces of pentane at = 1.27, 0.88) 13 C NMR (125 MHz, CDCl3) of 2k S41

42 2,5-Bis-(N-benzyl, N-(4-methylbenzenesulfonyl)buta-1,3-diyn-4-yl)thiophenediamide (8) 1 H NMR (400 MHz, CDCl3) of 8 (* traces of EtOAc at = 4.12, 2.05, 1.26) 13 C NMR (100 MHz, CDCl3) of 8 S42

43 H2O Bis-(N-benzyl, N-(4-methylbenzenesulfonyl))terthiophenediamide (9) 1 H NMR (500 MHz, CDCl3) of 9 13 C NMR (125 MHz, CDCl3) of 9 S43

44 Zoom of 13 C NMR (125 MHz, CDCl3) spectrum of 9 S44