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Suplementary Data

Synthesis of 3-iodothiophenes via Iodocyclization of (Z)-thiobutenynes

Amanda S. Santanaa, Diego B. Carvalhoa, Nadla S. Cassemiroa, Luiz H. Vianaa, Gabriela R. Hurtadoa, Marcos S. Amarala, Najla M. Kassaba, Palimécio G. Guerrero Jr.b, Sandro L. Barbosac, Miguel J. Dabdoubd, and Adriano C. M. Baroni a* a LASQUIM – Laboratório de Síntese e Química Medicinal, Centro de Ciências Biológicas e da Saúde e Centro de Ciências Exatas e Tecnológicas, Universidade Federal do Mato Grosso do Sul, UFMS, Campo Grande/MS, 79070-900, BrazilbDepartamento de Química e Biologia, DAQBi, Universidade Tecnológica Federal do Paraná, UTFPR, Curitiba/PR, 80230-901, BrazilcDepartamento de Farmácia-Bioquímica, Universidade Federal do Vale do Jequitinhonha e Mucuri, Diamantina/MG, 39100-000, BrazildDepartamento de Química, Av. Bandeirantes, 3900, Universidade de São Paulo, Ribeirão Preto/SP, 14040-901, Brazil

*Corresponding author. Tel.: +55-67-3345-7365; e-mail: [email protected]

List of Contents

1. General Remarks ……………………………………………………………………..S2

2. Typical procedure for the preparation of (Z)-thiobutenynes………………………S2

3. Typical procedure for the preparation of 3-iodothiophenes 3a-h………………….S2

4. Typical procedure for the preparation of 3-iodothiophenes 3i-k…………………S3

5. Typical procedure procedure for the Sonogashira cross-coupling reaction………S4

6.Typical procedure for reaction of 3-iodothiophene 3a with BuLi………………….S4

8. 1H NMR and 13C NMR Spectra for all compounds ……………………………

1. General Remarks

The 1H and 13C NMR spectra were recorded in CDCl3 solutions using a Brucker 75 MHz or 300 MHz spectrometer, as noted. Chemical shifts (δ) are expressed as parts per million (ppm) downfield from tetramethylsilane as the internal standard. GC/MS (using a HP-1 fused silica capillary column) and direct insertion spectra (EI) were measured at 70 eV. HR-ESI-MS measurements were carried out on a quadrupole time-of-flight instrument (UltrOTOF-Q, BrukerDaltonics, Billerica, MA). All reactions were performed under an atmosphere of dry nitrogen and monitored by TLC using prepared plates (Silica Gel 60

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F254 on aluminum). The chromatograms were examined under both 254 and 360 nm UV light or with the developing agent ethanolic vanillin. Merck silica gel (230-400 mesh) was used for chromatography. THF was distilled over sodium/benzophenone immediately before use. All solvents were dried and distilled before use according to the standard procedure. Flash column chromatography was performed on silica gel 60 (particle size 200-400 mesh ASTM, purchased from Aldrich, USA) and eluted with hexane or hexane/ethyl acetate in different ratios.

2. General procedure for the preparation of (Z)-thiobutenynes.1 To a solution of appropriate diynes 1a-k (5.0 mmol) in ethanol (35 ml) under reflux, we added dropwise a solution of C4H9SH (7.0 mmol) and 40% TBAOH in H2O (7.0 mmol) in 95% ethanol (35 mL) under a nitrogen atmosphere and vigorous stirring. The reaction mixture was stirred under reflux for 5 min (times varied depending upon the examples used),1 allowed to reach room temperature, diluted with ethyl acetate (60 mL) and washed with a saturated solution of NH4Cl (3 x 30 mL) and brine (3 x 30 mL). After the organic phase was dried over anhydrous MgSO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel, using hexane or hexane/ethyl acetate as the mobile phase.

3. General procedure for the preparation of 3-iodothiophenes 3a-h. To a solution of (Z)-thiobutenynes1 2a-h (2.0 mmol) in CH2Cl2 (12 ml), we added dropwise a solution of I2 (2.2 mmol) in CH2Cl2 (28 mL) under vigorous stirring. The reaction mixture was stirred for the times indicated in Table 2, diluted with CH2Cl2 (20 mL) and washed with a 10% solution of Na2S2O3 (3x30 mL) and brine (3x30 mL). After the organic phase was dried over anhydrous MgSO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel, using hexane as the mobile phase. 3.1. 3-iodo-2,5-diphenylthiophene 3a: as a yellow solid, mp = 42-44 °C, Yield: 92%. 1H NMR (300 MHz, CDCl3): δ 7.28 – 7.66 (m, 11H). 13C NMR (CDCl3, 75 MHz): δ 78.7; 125.6; 128.1; 128.4; 128.5; 129.0; 129.2; 132.3; 133.1; 134.2; 141.5; 145.1. GC/MS m/z 362 (M+) [100], 234, 202, 191, 165, 121, 77. HRMS Calcd for C16H11IS [M - H]: 360.9542; found: 360.9339.3.2. 3-iodo-2,5-bis(4-methoxyphenyl)thiophene 3b: as a yellow solid, mp = 93-95 ºC, Yield: 92%. 1H NMR (300 MHz, CDCl3): δ 7.55 (d, J 8.8 Hz, 2H); 7.47 (d, J 8.8 Hz, 2H); 7.19 (s, 1H); 6.95 (d, J 8.8 Hz, 2H); 6.90 (d, J 8.8 Hz, 2H); 3.84 (s, 3H); 3.82 (s, 3H); 13C NMR (CDCl3, 75 MHz): 55.3; 78.3; 113.9; 114.4; 126.0; 126.7; 126.9; 130.5; 131.1; 140.5; 144.5; 159.6; 159.7. HRMS Calcd for C18H15IO2S [M + H]: 422.9910; found: 422.9887.3.3. 3-iodo-2,5-bis(3,4-dimethoxyphenyl)thiophene 3c: as a yellow solid, mp = 145-147 ºC, Yield: 88%. 1H NMR (300 MHz, CDCl3): δ 3.88 (s, 3H); 3.90 (s, 3H); 3.92 (s, 3H); 3.93 (s, 3H); 6.85 (d, J 8.5 Hz, 1H); 6.89 (d, J 8.5 Hz, 1H); 7.03 (d, J 1.9 Hz, 1H); 7.10 (dd, J 8.5 and 1.9 Hz, 1H); 7.14 – 7.17 (m, 2H); 7.19 (s, 1H). 13C NMR (CDCl3, 75 MHz): 55.9; 78.1; 108.9; 110.9; 111.5; 112.3; 118.2; 121.8; 126.1; 126.7; 131.2; 140.6; 144.5; 148.6; 149.2. HRMS Calcd for C20H19IO4S [M + H]: 483.0121; found: 483.0150.3.4. 3-iodo-2,5-bis(4-chlorophenyl)-thiophene 3d: as a yellow solid, mp = 146-148 ºC, Yield: 77%. 1H NMR (300 MHz, CDCl3): δ 7.55 (d, J 8.6 Hz, 2H); 7.47 (d, J 8.6 Hz, 2H);

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7.39 (d, J 8.6 Hz, 2H); 7.34 (d, J 8.6 Hz, 2H); 7.29 (s, 1H); 13C NMR (CDCl3, 75 MHz): 79.3; 126.8; 128.9; 129.3; 130.4; 131.4; 132.4; 132.7; 134.1; 134.7; 140.5; 144.1. GC/MS m/z 430 (M+) [100]; 268; 232; 155.3.5. 2,5-dibutyl-3-iodothiophene 3e: as a yellow oil, Yield: 65%. 1H NMR (300 MHz, CDCl3): δ 6.61 (s, 1H). 2.66 – 2.73 (m, 4H); 1.54 – 1.64 (m, 4H); 1.29 – 1.44 (m, 4H); 0.88 – 0.95 (m, 6H); 13C NMR (CDCl3, 75 MHz): 13.8; 13.9; 22.1; 22.2; 29.7; 31.8; 33.1; 33.4; 78.2; 131.0; 141.4; 144.5. GC/MS m/z 322 (M+); 279 (100); 237; 223; 195; 153; 110. HRMS Calcd for C12H19IS [M - H]: 321.0168; found: 321.0174.3.6. 2,5-dihexyl-3-iodothiophene 3f: as a yellow oil, Yield: 61%. 1H NMR (300 MHz, CDCl3): δ 0.84 – 0.88 (m, 6H); 1.29 (m, 12H); 1.60 (m, 4H); 2.64 – 2.72 (m, 4H); 6.61 (s, 1H). 13C NMR (CDCl3, 75 MHz): δ 14.1; 22.6; 28.7; 30.0; 30.9; 31.3; 31.5; 32.1; 78.2; 130.9; 141.3; 144.5. GC/MS m/z 378 (M+); 307 (100); 251; 237; 223; 181; 110. HRMS Calcd for C16H27IS [M - H]: 377.0794; found: 377.0801.3.7. 2-(5-(4-chlorophenyl)-4-iodothiophen-2-yl)propan-2-ol 3g: as a light-red oil, Yield: 78%. 1H NMR (300 MHz, CDCl3): δ 1.64 (s, 6H); 2.23 (sl, 1H); 6.94 (s, 1H); 7.36 (d, J 8.4 Hz, 2H); 7.49 (d, J 8.4 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 31.9; 71.2; 77.5; 128.6; 130.4; 131.3; 132.7; 134.3; 139.3; 155.5. CG/MS m/z: 378; 363 (100); 360; 345; 236; 221; 59. HRMS Calcd for C13H12ClIS [M – H2O]: 360.9309; found: 360.9318.3.8. 2-(4-iodo-5-phenylthiophen-2-yl)propan-2-ol 3h: as a light-red oil, Yield: 84%. 1H NMR (300 MHz, CDCl3): δ 1.65 (s, 6H); 2.19 (sl, 1H); 6.96 (s, 1H); 7.35 – 7.43 (m, 3H); 7.55 – 7.58 (m, 2H). 13C NMR (CDCl3, 75 MHz): δ 31.9; 71.2; 77.0; 128.2; 128.4; 129.2; 131.2; 134.3; 140.7; 155.1. CG/MS m/z: 344; 329; 326 (100); 311; 184; 115; 77; 59. HRMS Calcd for C13H13IS [M – H2O]: 326.9698; found: 326.9691.

4. Typical procedure for the preparation of 3-iodothiophenes 3i-k.To a solution of (Z)-1-buthylthio-1,4-diorganyl-1-buten-3-yne 2k (2.0 mmol) in 1,2-dichloroethane (12 ml) at 70 °C, we added dropwise a solution of I2 (2.2 mmol) in 1,2-dichloroethane (28 mL) under vigorous stirring. The reaction mixture was stirred for 1-2 h (see times in Table 2) at 70 °C, diluted with 1,2-dichloroethane (20 mL) and washed with a 10% solution of Na2S2O3 (3 x 30 mL) and brine (3 x 30 mL). After the organic phase was dried over anhydrous MgSO4, the solvent was removed under reduced pressure and the residue purified by flash chromatography on silica gel, using hexane as the mobile phase, to give pure: 4.1. 2-(n-butyl)-3-iodotiophene 3i: as a light-yellow oil, Yield: 68%. 1H NMR (300 MHz, CDCl3): δ 0.98 (t, J 7.1 Hz, 3H); 1.44 (sex, J 7.1 Hz, 2H), 1.67 (quint, J 7.2 Hz, 2H); 2.80 (t, J 7.6 Hz, 2H); 6.98 (d, J 5.3 Hz, 1H); 7.12 (d, J 5.13 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 13.8; 22.1; 31.6; 33.0; 79.3; 124.3; 134.4; 143.8. CG/MS m/z: 266; 223 (100); 139; 97; 96; 45.4.2. 2-(n-hexyl)-3-iodotiophene 3j: as a light-yellow oil, Yield: 65%. 1H NMR (300 MHz, CDCl3): δ 0.94 (t, J 7.3 Hz, 3H); 1.34 – 1.46 (m, 4H); 1.58 – 1.68 (m, 4H); 2.75 (t, J 7.3 Hz, 2H); 6.96 (d, J 5.3 Hz, 1H); 7.11 (d, J 5.3 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ 14.0; 22.5; 28.7; 30.9; 31.9; 33.0; 79.2; 124.3; 134.5; 144.0. CG/MS m/z: 294; 223; 167; 97 (100); 96; 45.4.3. 2-fenyl-3-iodotiophene 3k: as a light-yellow oil, Yield: 80%. 1H NMR (300 MHz, CDCl3): δ 7.13 (d, J 5.3 Hz, 1H); 7.28 (d, J 5.3 Hz, 1H); 7.40 – 7.50 (m, 3H); 7.64 – 7.67

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(m, 2H). 13C NMR (CDCl3, 75 MHz): δ 78.1; 126.7; 128.3; 128.4; 129.3; 134.1; 136.5; 142.2. CG/MS m/z: 286; 159; 115 (100); 77; 45.

5. Typical procedure for the Sonogashira cross-coupling reaction2. To a solution of 3a (1.0 mmol), PdCl2(PPh3)2 (0.05 mmol), and CuI (0.1 mmol), 1-alkyne (2.0 mmol), in THF (2.0 mL) at 25 °C, under a nitrogen atmosphere was added dropwise, a solution of triethylamine (5 ml). The reaction was stirred under reflux for 24 h, extracted with ethyl acetate (3 x 15.0 mL) and washed with brine (4 x 10 mL). Next, the organic layer was dried over MgSO4, the solvent evaporated under vacuum, and the crude products were purified by flash silica-gel chromatography using hexane as the mobile phase.5.1. 3-(hept-1-ynyl)-2,5-diphenylthiophene 11a: as a light-yellow oil, Yield: 82%. 1H NMR (300 MHz, CDCl3): δ 0.91 (t, J 7.0 Hz, 3H); 1.39 (m, 4H); 1.59 (m, 4H); 2.42 (t, J 7.0 Hz, 2H); 7.34 (m, 7H); 7.59 (dd, J 7.0 Hz and J 1.50 Hz, 2H); 7.91 (dd, J 7.3Hz and J 1.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz): δ 14.0; 19.6; 22.2; 28.3; 31.1; 92.8; 119.3; 125.6; 127.4; 127.8; 127.8; 127.9; 128.5; 129.0; 133.7; 133.9; 141.5; 143.7. HRMS Calcd for C23H22 S [M + H]: 331.1514; found: 331.1513.5.2. 2,5-diphenyl-3-(2-phenylethynyl)thiophene 11b: as a light-yellow oil, Yield: 78%. 1H NMR (300 MHz, CDCl3): δ 7.39 (m, 12H); 7.77 (dd, J 7.00 Hz and J 1.4 Hz, 2H); 7.98 (dd, J 7.00 Hz and J 1.4 Hz, 2H); 13C NMR (CDCl3, 75 MHz): δ 85.6; 91.5; 118.6; 123.4; 125.7; 127.4; 127.7; 128.0; 128.2; 128.3; 128.4; 128.6; 129.0; 133.6; 133.8; 142.0. HRMS Calcd for C24H16 S [M + H]: 337.1045; found: 337.1044.

6. Typical procedure for reaction of 3a with BuLi.3 To a two-neck round-bottomed flask under nitrogen atmosphere, containing a solution of

3a (1.0 mmol) in THF (5 mL), was added n-BuLi (1.2 mmol, 2.40 M in hexane) dropwise at 0 °C. After the end of addition (3 min), the reaction mixture was stirred for 30 min, and then water (2 mL) was added dropwise under N2. The reaction mixture was diluted with ethyl acetate (~40 mL) and washed with brine (3 x 40 mL). The organic phase was dried over MgSO4 and filtered. The solvent was removed under reduced pressure, and the residue purified by flash chromatography on silica gel, using hexane as the mobile phase. 6.1. 2,5-Diphenylthiophene 12: as white solid, Yield: 75%. 1H NMR (300 MHz, CDCl3): δ 7.27-7.30 (m, 4H); 7.39 (dd, J 7.7 Hz and J 7.3 Hz, 4H); 7.63 (d, J 7.3 Hz, 4H); 13C NMR (CDCl3, 75 MHz): δ 124.0; 125.6; 127.5; 128.9; 134.3; 143.6. The spectra are in accordance with reference 4.

7. References:

1. Santana, A. S.; Carvalho, D. B.; Casemiro, N. S.; Hurtado, G. R.; Viana, L. H.; Kassab, N. M.; Barbosa, S. L.; Marques, F. A.; Guerrero Jr., P. G.; Baroni, A. C. M. Tetrahedron Lett. 2012, 53, 5733.

2. Vuligonda, V.; Thacher, S. M.; Chandraratna, R. A. S. J. Med. Chem. 2001, 44, 2298.3. Guerrero Jr., P. G.; Dabdoub, M. J.; Marques, F. A.; Wosch, C. L.; Baroni, A. C. M.;

Ferreira, A. G. Synth. Commun. 2008, 38, 4379.4. Jiang, H.; Zeng, W.; Li, Y.; Wu, W.; Huang, L.; Fu, W. J. Org. Chem. 2012, 77, 5179.

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8. 1H NMR and 13C NMR spectra for all compounds

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