A Closer Look at the Bromine-Lithium Exchange with

SUPPRTIG IFRMATI A Closer Look at the Bromine-Lithium Exchange with tert-butyllithium in an Aryl Sulfonamide Synthesis Christopher Waldmann,*, tmar Schober, Günter Haufe, and Klaus Kopka, Department of uclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany ew address: Radiopharmaceutical Chemistry, German Cancer Research Center (dkfz), Im euenheimer Feld 280, D-69120 Heidelberg, Germany rganic Chemistry Institute, University of Münster, Corrensstr. 40, D-48149 Münster, Germany S1

Contents 1. General Remarks S3 2. Experimental Section S4 2.1 Synthesis of non-commercial aryl bromides S4 2.2 Synthesis of aryl sulfonyl chlorides S7 2.3 GC-MS assisted protonation assay S8 2.4 Long-term measurement of the stability of 5-bromo-1-(triisopropylsilyl)-1Hpyrrolo[2,3-b]pyridine (1) after bromine-lithium exchange S9 2.5 Synthesis of aryl sulfonamides S10 3. MR Spectroscopy S17 4. GC-MS S30 S2

1. General Remarks All chemicals, reagents and solvents for the synthesis of the compounds were analytical grade, purchased from commercial sources and used without further purification unless otherwise specified. Bis(sulphur dioxide) 1,4-diazabicyclo[2.2.2]octane (DABS) was prepared according to Santos and Mello. 1 All air and moisture-sensitive reactions were performed under argon atmosphere. Solvents were purified and dried by literature methods where necessary. The molarity of t-buli was frequently determined by titration using the method of Burchat et al. in the solvent used for the experiments. 2 The melting points (mp) are uncorrected and were determined in capillary tubes on a Stuart Scientific SMP3 capillary melting point apparatus. Column chromatography was performed on Merck silica gel 60 (0.040 0.063 mm). Thin layer chromatography (TLC) was carried out on silica gel-coated polyester backed TLC plates (Polygram, SIL G/UV 254, Macherey-agel) using solvent mixtures of cyclohexane (CH) and ethyl acetate (EA). Compounds were visualized by UV light (254 nm). MR spectra were recorded in CDCl 3 on a Bruker ARX300, a Bruker DPX300 ( 1 H MR, 300 MHz, 13 C MR, 75MHz, 19 F MR, 282 MHz) and a Bruker AMX 400 ( 1 H MR, 400 MHz, 13 C MR, 100 MHz). TMS ( 1 H) and CDCl 3 ( 13 C) were used as internal standards and all chemical shift values are given in ppm (δ). Values of the coupling constant J are given in Hertz (Hz); the following abbreviations are used for the description of 1 H MR spectra: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), doublet of doublets (dd) and septet (sep). The chemical shifts of complex multiplets are given as the range of their occurrence. Exact mass analyses were conducted on a Bruker MicroTof apparatus. GC-MS measurements were performed on a GCMS-QP2010 Ultra (Shimadzu) instrument with Helium as the carrier gas. 1 Santos, P. S.; Mello, M. T. S. J. Mol. Struct. 1988, 178, 121. 2 Burchat, A. F.; Chong, J. M.; ielsen,. J. rganomet. Chem. 1997, 542, 281. S3

2. Experimental Section 2.1 Synthesis of non-commercial aryl bromides General procedure for TIPS-protection of brominated 7-Azaindols (1, 3, 4) A 50 ml Schlenk tube was charged with sodium hydride (95% pure, 0.097 g, 3.84 mmol) and dry THF (4 ml) under argon. The suspension was cooled to 0 C in an ice bath and the corresponding brominated 7-azaindole (2.95 mmol) was slowly added as a solution in dry THF (6 ml). After 15 min, chloro-triisopropylsilane (95% pure, 0.599 g, 2.95 mmol) was added as a solution in dry THF (2 ml) at 0 C and the ice bath was removed. At room temperature saturated aqueous solution of ammonium chloride (30 ml) was added and the resulting mixture was extracted with cyclohexane (2 25 ml). The combined organic phases were dried over MgS 4, and evaporated. The residue was purified by flash column chromatography. 5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1). btained from 5-bromo-1H-pyrrolo[2,3-b]pyridine (96% pure, 0.6 g, 2.95 mmol). Column chromatographic purification (Si 2, CH/EtAc, 19:1) yielded a colorless oil, which had to be stored at -32 C to prevent decomposition [949 mg, 91% yield]. It solidifies over night to become a white, noncrystalline solid. 1 H MR (300 MHz, CDCl 3 ): δ 1.11 (d, 18 H, CH 3, 3 J H,H = 7.6 Hz), 1.83 (sep, 3 H, S4

CH, 3 J H,H = 7.6 Hz), 6.49 (d, 1 H, CH, 3 J H,H = 3.5 Hz), 7.30 (d, 1 H, CH, 3 J H,H = 3.5 Hz), 7.98 (d, 1 H, CH, 4 J H,H = 2.3 Hz), 8.27 (d, 1 H, CH, 4 J H,H = 2.3 Hz). 13 C-MR (75 MHz, CDCl 3 ): δ 12.3, 18.2, 102.6, 112.2, 124.2, 129.9, 132.8, 142.9, 152.3. HRMS-ESI: calcd. for C 16 H 25 Br 2 SiH + ([M+H] + ), 355.1023/353.1044; found 355.1017/353.1039. Calcd. for C 16 H 25 Br 2 Sia + ([M+a] + ), 377.0843/375.0863; found 377.0842/375.0861. 4-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3) btained from 4-bromo-1H-pyrrolo[2,3-b]pyridine (96% pure, 0.6 g, 2.95 mmol). Column chromatographic purification (Si 2, CH/EtAc, 19:1) yielded a colorless oil, which had to be stored at -32 C to prevent decomposition [952 mg, 91% yield]. It solidifies over night to become a pale-grey, non-crystalline solid. 1 H MR (300 MHz, CDCl 3 ): δ 1.12 (d, 18 H, CH 3, 3 J H,H = 7.5 Hz), 1.85 (sep, 3 H, CH, 3 J H,H = 7.5 Hz), 6.60 (d, 1 H, CH, 3 J H,H = 3.5 Hz), 7.22 (d, 1 H, CH, 3 J H,H = 5.1 Hz), 7.35 (d, 1 H, CH, 3 J H,H = 3.5 Hz), 8.05 (d, 1 H, CH, 3 J H,H = 5.1 Hz). 13 C MR (75 MHz, CDCl 3 ): δ 12.4, 18.2, 103.1, 119.2, 124.0, 124.2, 131.8, 142.6, 153.6. HRMS-ESI: calcd. for C 16 H 25 Br 2 SiH + ([M+H] + ), 355.1023/353.1044; found 355.1028/353.1048. 3-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (4) btained from 3-bromo-1H-pyrrolo[2,3-b]pyridine (97% purity, 0.6 g, 2.95 mmol). Column chromatographic purification (Si 2, CH/EtAc, 19:1) yielded a colorless oil, which had to be stored at S5

-32 C to prevent decomposition [1.013 g, 97% yield]. It solidifies over night to become a pale-grey, non-crystalline solid. 1 H MR (300 MHz, CDCl 3 ): δ 1.12 (d, 18 H, CH 3, 3 J H,H = 7.5 Hz), 1.84 (sep, 3 H, CH, 3 J H,H = 7.5 Hz), 7.11 (dd, 1 H, CH, 3 J H,H = 7.9 Hz, 3 J H,H = 4.7 Hz), 7.29 (s, 1 H, CH), 7.81 (dd, 1 H, CH, 3 J H,H = 7.9 Hz, 4 J H,H = 1.6 Hz), 8.29 (dd, 1 H, CH, 3 J H,H = 4.7 Hz, 4 J H,H = 1.6 Hz). 13 C MR (75 MHz, CDCl 3 ): δ 12.4, 18.2, 91.3, 116.7, 121.7, 126.7, 129.8, 143.6, 152.6. HRMS-ESI: calcd. for C 16 H 25 Br 2 SiH + ([M+H] + ), 355.1023/353.1044; found 355.1022/353.1043. 5-Bromo-1-propyl-1H-pyrrolo[2,3-b]pyridine (5). To a solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (96% pure, 3.00 g, 14.6 mmol) in dimethylacetamide (50 ml) was carefully added sodium hydride (60% suspension in oil, 0.76 g, 19.0 mmol). The mixture was stirred at rt for 30 min and n-propyl bromide (1.60 ml, 17.5 mmol) was slowly added as a solution in dimethylacetamide (10 ml). After additional 2 h water (120 ml) was added and the resulting mixture was extracted with DCM (2 100 ml). The combined organic phases were washed with water, dried over MgS 4, and evaporated. Column chromatographic purification (Si 2, CH/EtAc, 6:1) yielded a colorless oil, which had to be stored at -32 C to prevent decomposition [3.387 g, 97% yield]. 1 H MR (300 MHz, CDCl 3 ): δ 0.90 (t, 3 H, CH 3, 3 J H,H = 7.4 Hz), 1.92 1.79 (m, 2 H, CH 2 ), 4.23 4.16 (m, 2 H, CH 2 ), 6.36 (d, 1 H, CH, 3 J H,H = 3.5 Hz), 7.19 (d, 1 H, CH, 3 J H,H = 3.5 Hz), 7.98 (d, 1 H, CH, 4 J H,H = 2.2 Hz), 8.31 (d, 1 H, CH, 4 J H,H = 2.2 Hz). 13 C MR (75 MHz, CDCl 3 ): δ 11.4, 23.7, 46.5, 98.9, 111.4, 122.1, 129.5, 130.7, 143.2, 145.9. HRMS-ESI: calcd. for C 10 H 11 Br 2 H + ([M+H] + ), 241.0158/239.0178; found 241.0160/239.0177. S6

2.2 Synthesis of aryl sulfonyl chlorides 1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonyl chloride (2) A 50 ml Schlenk tube was charged with 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3- b]pyridine (1) (177 mg, 0.5 mmol) and dry THF (5 ml) under argon. The solution was cooled to - 80 C in an ethanol/nitrogen cooling bath and 1.0 equivalent t-buli (1.56 M, 0.32 ml) was added dropwise. After 10 min the reaction mixture was warmed up to -75 C and DABC-bis(sulfur dioxide) (120 mg, 0.5 mmol) was added at once. The cooling bath was removed after 30 min and the reaction mixture warmed up to ambient temperature. The THF solvent was removed under reduced pressure and dry DCM (8 ml) was added. CS (80 mg, 0.6 mmol) was slowly added as a solution in dry DCM (2 ml). After 10 min the reaction mixture was filtered over a bed of silica gel (2 cm) with additional ethyl acetate (10 ml). The solvents were evaporated under reduced pressure. Column chromatographic purification (Si 2, CH/EtAc, 49:1) yielded a colorless oil [108 mg, 58% yield]. It crystallizes over night to become a white, crystalline solid. Mp: 57 58 C. 1 H MR (300 MHz, CDCl 3 ): δ 1.13 (d, 18H, CH 3, 3 J H,H = 7.6 Hz), 1.87 (sep, 3H, CH, 3 J H,H = 7.6 Hz), 6.76 (d, 1H, CH, 3 J H,H = 3.6 Hz), 7.52 (d, 1H, CH, 3 J H,H = 3.6 Hz), 8.51 (d, 1H, CH, 4 J H,H = 2.4 Hz), 8.90 (d, 1H, CH, 4 J H,H = 2.4 Hz). 13 C MR (75 MHz, CDCl 3 ): δ 12.3, 18.1, 105.1, 121.7, 127.7, 133.8, 135.3, 140.8, 155.9. HRMS-ESI: calcd. for C 17 H 28 2 3 SSia + ([M+CH 3 +a-cl] + ), 391.1483; found 391.1489. S7

2.3 GC-MS assisted protonation assay Method A: A 50 ml Schlenk tube was charged with the corresponding aryl bromide (0.5 mmol) and dry THF (5 ml) under argon. The solution was cooled to -80 C in an ethanol/nitrogen cooling bath and the respective amount of t-buli (1.0 to 2.0 eq) was added dropwise. After 10 min the reaction mixture was warmed up to -75 C and methanol (0.3 ml) was added at once. The cooling bath was removed and after warming to room temperature the reaction mixture was filtered over a bed of silica gel (2 cm) with additional THF (2 3 ml). A small sample (100 µl) was diluted with methanol (900 µl) and analyzed by GC-MS. Method B: A 50 ml Schlenk tube was charged with ah (95% pure, 0.7 mmol) and dry THF (5 ml) under argon. The suspension was cooled to 0 C and the corresponding aryl bromide (0.5 mmol) was added dropwise as a solution in 2 ml dry THF. After 30 min the mixture was cooled to -80 C in an ethanol/nitrogen cooling bath and the respective amount of t-buli (1.0 to 2.0 eq.) was added dropwise. After 10 min the reaction mixture was warmed up to -75 C and acetic acid (0.3 ml) was added at once. The cooling bath was removed and after warming to room temperature the reaction mixture was filtered over a bed of silica gel (2 cm) with additional THF (2 3 ml). A small sample (100 µl) was diluted with methanol (900 µl) and analyzed by GC-MS. S8

2.4 Long-term measurement of the stability of 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo [2,3-b]pyridine (1) after bromine-lithium exchange A 50 ml Schlenk tube was charged with 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3- b]pyridine (1) (177 mg, 0.5 mmol) and dry THF (5 ml) under argon. The solution was cooled to - 80 C in an ethanol/nitrogen cooling bath and 1.0 equivalent t-buli (1.56 M, 0.32 ml) was added dropwise. The reaction mixture gradually warmed up to ambient temperature and was then stirred for 24 hours. Methanol (6 ml) was added. A small sample (100 µl) was diluted with methanol (900 µl) and analyzed by GC-MS. After addition of water (10 ml) the mixture was extracted with DCM (20 ml). The combined organic phases were dried over MgS 4, evaporated and a colorless oil [134 mg, 98% yield] was yielded. It crystallizes over night to become a white, non crystalline solid. 1 H MR (300 MHz, CDCl 3 ): δ 1.12 (d, 18H, CH 3, 3 J H,H = 7.5 Hz), 1.86 (sep, 3H, CH, 3 J H,H = 7.5 Hz), 6.54 (d, 1H, CH, 3 J H,H = 3.6 Hz), 7.02 (dd, 1H, 3 J = 7.8, 3 J = 4.7), 7.30 (d, 1H, CH, 3 J H,H = 3.6 Hz), 7.86 (dd, 1H, CH, 3 J H,H = 7.8, 4 J H,H = 1.6 Hz), 8.25 (dd, 1H, CH, 3 J H,H = 4.7, 4 J H,H = 1.6 Hz). MS-EI: m/z 274 (M+, 76), 231 (87), 189 (66), 175 (11), 161 (30), 147 (100), 118 (7), 59 (7). S9

2.5 Synthesis of aryl sulfonamides (10, 11, 12, 13, 14, 15, 16, 17) Method A: A 50 ml Schlenk tube was charged with the corresponding aryl bromide (0.5 mmol) and dry THF (5 ml) under argon. The solution was cooled to -80 C in an ethanol/nitrogen cooling bath and the respective amount of t-buli (determined for any corresponding aryl bromide) was added dropwise. After 10 min the reaction mixture was warmed up to -75 C and DABC-bis(sulfur dioxide) (120 mg, 0.5 mmol) was added at once. The cooling bath was removed after 30 min and the reaction mixture warmed up to room temperature. The THF solvent was removed under reduced pressure and dry DCM (8 ml) was added. CS (80 mg, 0.6 mmol) was slowly added as a solution in dry DCM (2 ml). In a separate flask Piperidine (43 mg, 0.5 mmol) was dissolved in dry DCM (2 ml) and,-diisopropylethylamine (65 mg, 0.5 mmol) was added. This solution was then added to the reaction mixture directly. After the addition of water (20 ml) the mixture was extracted with DCM (2 20 ml). The combined organic phases were dried over MgS 4, and evaporated. The residue was purified by flash column chromatography. S10

Method B: A 50 ml Schlenk tube was charged with ah (95% pure), 0.7 mmol) and dry THF (5 ml) under argon. The suspension was cooled to 0 C and the corresponding aryl bromide (0.5 mmol) was added dropwise as a solution in 2 ml dry THF. After 30 min the mixture was cooled to -80 C in an ethanol/nitrogen cooling bath and the respective amount of t-buli (determined for any corresponding aryl bromide) was added dropwise. After 10 min the reaction mixture was warmed up to -75 C and DABC-bis(sulfur dioxide) (120 mg, 0.5 mmol) was added at once. The cooling bath was removed after 30 min and the reaction mixture warmed up to room temperature. The THF solvent was removed under reduced pressure and dry DCM (8 ml) was added. CS (80 mg, 0.6 mmol) was slowly added as a solution in dry DCM (2 ml). In a separate flask Piperidine (43 mg, 0.5 mmol) was dissolved in dry DCM (2 ml) and,-diisopropylethylamine (65 mg, 0.5 mmol) was added. This solution was then added to the reaction mixture directly. After the slow addition of water (20 ml) the mixture was extracted with DCM (2 20 ml). The combined organic phases were dried over MgS 4, and evaporated. The residue was purified by flash column chromatography. 5-(Piperidin-1-ylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (10) TIPS S Method A. btained from 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1) (177 mg, 0.5 mmol). For the bromine-lithium exchange 1.0 equivalent t-buli (1.56 M, 0.32 ml) was used. S11

Column chromatographic purification (Si 2, CH/EtAc, 9:1) yielded a colorless oil [160 mg, 76% yield]. It crystallizes over night to become a white, crystalline solid. Mp: 140 141 C. 1 H MR (400 MHz, CDCl 3 ): δ 1.10 (d, 18H, CH 3, 3 J H,H = 7.6 Hz), 1.44 1.39 (m, 2H, CH 2 ), 1.70 1.61 (m, 4H, CH 2 ), 1.85 (sep, 3H, CH, 3 J H,H = 7.6 Hz), 3.06 3.00 (m, 4H, CH 2 ), 6.68 (d, 1H, CH, 3 J H,H = 3.5 Hz), 7.43 (d, 1H, CH, 3 J H,H = 3.5 Hz), 8.25 (d, 1H, CH, 4 J H,H = 2.2 Hz), 8.62 (d, 1H, CH, 4 J H,H = 2.2 Hz). 13 C MR (101 MHz, CDCl 3 ): δ 12.3, 18.2, 23.6, 25.3, 47.1, 104.2, 121.6, 124.8, 128.1, 133.8, 141.6, 155.3. HRMS-ESI: calcd. for C 21 H 35 3 2 SSiH + ([M+H] + ), 422.2292; found 422.2296. Calcd. for C 21 H 35 3 2 SSia + ([M+a] + ), 444.2111; found 422.2116 4-(Piperidin-1-ylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (11) Method A. btained from 4-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3) (177 mg, 0.5 mmol). For the bromine-lithium exchange 1.0 equivalent t-buli (1.56 M, 0.32 ml) was used. Column chromatographic purification (Si 2, CH/EtAc, 9:1) yielded a colorless oil [131 mg, 62% yield]. It crystallizes over night to become a white, crystalline solid. Mp: 115 116 C. 1 H MR (400 MHz, CDCl 3 ): δ 1.10 (d, 18H, CH 3, 3 J H,H = 7.6 Hz), 1.44 1.39 (m, 2H, CH 2 ), 1.65 1.59 (m, 4H, CH 2 ), 1.85 (sep, 3H, CH, 3 J H,H = 7.6 Hz), 3.13 3.07 (m, 4H, CH 2 ), 7.00 (d, 1H, CH, 3 J H,H = 3.5 Hz), 7.36 (d, 1H, CH, 3 J H,H = 4.9 Hz), 7.45 (d, 1H, CH, 3 J H,H = 3.5 Hz), 8.37 (d, 1H, CH, 3 J H,H = 4.9 Hz). 13 C MR (101 MHz, CDCl 3 ): δ 12.3, 18.2, 23.6, 25.4, 47.0, 103.7, 114.7, 118.9, 134.1, 135.0, 141.8, 155.4. HRMS-ESI: calcd. for C 21 H 35 3 2 SSiH + ([M+H] + ), 422.2292; found 422.2291. Calcd. for C 21 H 35 3 2 SSia + ([M+a] + ), 444.2111; found 422.2111 S12

3-(Piperidin-1-ylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (12) Method A. btained from 3-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (4) (177 mg, 0.5 mmol). For the bromine-lithium exchange 1.0 equivalent t-buli (1.56 M, 0.32 ml) was used. Column chromatographic purification (Si 2, CH/EtAc, 9:1) yielded a colorless oil [103 mg, 49% yield]. It crystallizes over night to become a white, non crystalline solid. A small amount of byproduct could not be separated by column chromatography. It was identified by GC-MS to be TIPSH. 1 H MR (400 MHz, CDCl 3 ): δ 1.10 (d, 18H, CH 3, 3 J H,H = 7.6 Hz), 1.41 1.34 (m, 2H, CH 2 ), 1.66 1.59 (m, 4H, CH 2 ), 1.88 (sep, 3H, CH, 3 J H,H = 7.6 Hz), 3.05 2.99 (m, 4H, CH 2 ), 7.17 (dd, 1H, CH, 3 J H,H = 4.7 Hz, 3 J H,H = 8.0 Hz), 7.74 (s, 1H, CH), 8.19 (dd, 1H, CH, 4 J H,H = 1.7 Hz, 3 J H,H = 8.0 Hz), 8.34 (dd, 1H, CH, 4 J H,H = 1.7 Hz, 3 J H,H = 4.7 Hz). 13 C MR (101 MHz, CDCl 3 ): δ 12.2, 18.1, 23.6, 25.3, 46.9, 112.1, 118.0, 119.0, 128.4, 135.9, 144.3, 153.3. HRMS-ESI: calcd. for C 21 H 35 3 2 SSiH + ([M+H] + ), 422.2292; found 422.2289. Calcd. for C 21 H 35 3 2 SSia + ([M+a] + ), 444.2111; found 422.2108. 5-(Piperidin-1-ylsulfonyl)-1-propyl-1H-pyrrolo[2,3-b]pyridine (13) Method A. btained from 5-bromo-1-propyl-1H-pyrrolo[2,3-b]pyridine (5) (120 mg, 0.5 mmol). For the bromine-lithium exchange 1.0 equivalent t-buli (1.56 M, 0.32 ml) was used. Column chromatographic purification (Si 2, CH/EtAc, 4:1) yielded a colorless oil [106 mg, 69% yield]. It crystallizes over night to become a white, crystalline solid. Mp: 96 97 C. 1 H MR (400 MHz, S13

CDCl 3 ): δ 0.93 (t, 3H, CH 3, 3 J H,H = 7.4 Hz), 1.40 1.33 (m, 2H, CH 2 ), 1.66 1.59 (m, 4H, CH 2 ), 1.94 1.84 (m, 2H, CH 2 ), 3.02 2.96 (m, 4H, CH 2 ), 4.30 4.24 (m, 2H, CH 2 ), 6.56 (d, 1H, CH, 3 J H,H = 3.5 Hz), 7.35 (d, 1H, CH, 3 J H,H = 3.5 Hz), 8.26 (d, 1H, CH, 3 J H,H = 2.1 Hz), 8.65 (dd, 1H, CH, 3 J H,H = 2.1). 13 C MR (101 MHz, CDCl 3 ): δ 11.4, 23.5, 23.7, 25.2, 46.7, 47.0, 101.0, 119.6, 124.3, 129.0, 130.7, 141.9, 148.6. HRMS-ESI: calcd. for C 15 H 21 3 2 SH + ([M+H] + ), 308.1427; found 308.1427. Calcd. for C 15 H 21 3 2 Sa + ([M+a] + ), 330.1247; found 330.1245. 3-Methoxy-5-(piperidin-1-ylsulfonyl)pyridine (14) Method A. btained from 3-bromo-5-methoxypyridine (6) (97 mg, 0.5 mmol). For the bromine-lithium exchange 1.6 equivalents t-buli (1.56 M, 0.51 ml) were used. Column chromatographic purification (Si 2, CH/EtAc, 2:1) yielded a colorless oil [81 mg, 63% yield]. It crystallizes over night to become a white, crystalline solid. Mp: 93 95 C. 1 H MR (400 MHz, CDCl 3 ): δ 1.46 1.39 (m, 2H, CH 2 ), 1.67 1.60 (m, 4H, CH 2 ), 3.04 2.99 (m, 4H, CH 2 ), 3.90 (s, 3H, CH 3 ), 7,46 (dd, 1H, CH, 4 J H,H = 1.7 Hz, 4 J H,H = 2.8 Hz), 8.47 (d, 1H, CH, 4 J H,H = 2.8 Hz), 8.53 (d, 1H, CH, 4 J H,H = 1.7 Hz) 13 C MR (101 MHz, CDCl 3 ): δ 23.5, 25.2, 46.9, 56.11, 118.5, 133.5, 140.2, 142.0, 155.6. HRMS-ESI: calcd. for C 11 H 16 2 3 SH + ([M+H] + ), 257.0954; found 257.0952. Calcd. for C 15 H 21 3 2 Sa + ([M+a] + ), 279.0774; found 279.0771. S14

1-((2,3,4-Trimethoxyphenyl)sulfonyl)piperidine (15) Method A. btained from 1-bromo-2,3,4-trimethoxybenzene (7) (124 mg, 0.5 mmol). For the bromine-lithium exchange 1.4 equivalents t-buli (1.56 M, 0.45 ml) were used. Column chromatographic purification (Si 2, CH/EtAc, 3:1) yielded a colorless oil [114 mg, 72% yield]. 1 H MR (400 MHz, CDCl 3 ): δ 1.49 1.31 (m, 2H, CH 2 ), 1.62 1.55 (m, 4H, CH 2 ), 3.14 8.08 (m, 4H, CH 2 ), 3.87 (s, 3H, CH 3 ), 3,89 (s, 3H, CH 3 ), 3.94 (s, 3H, CH 3 ), 6.69 (d, 1H, CH, 3 J H,H = 9.0 Hz), 7.54 (d, 1H, CH, 3 J H,H = 9.0 Hz). 13 C MR (101 MHz, CDCl 3 ): δ 23.9, 25.7, 46.8, 56.2, 61.0, 61.8, 106.4, 124.4, 126.4, 143.1, 152.0, 157.5. HRMS-ESI: calcd. for C 14 H 21 5 SH + ([M+H] + ), 316.1213; found 316.1214. Calcd. for C 14 H 21 5 Sa + ([M+a] + ), 338.1033; found 338.1033. 1-((1-(Triisopropylsilyl)-1H-pyrrol-3-yl)sulfonyl)piperidine (16) Method A. btained from 3-bromo-1-(triisopropylsilyl)-1H-pyrrole (8) (156 mg, 0.5 mmol). For the bromine-lithium exchange 1.2 equivalents t-buli (1.56 M, 0.38 ml) were used. Column chromatographic purification (Si 2, CH/EtAc, 6:1) yielded a colorless oil [128 mg, 69% yield]. 1 H MR (400 MHz, CDCl 3 ): δ 1.09 (d, 18H, CH 3, 3 J H,H = 7.5 Hz), 1.50 1.37 (m, 5H, CH 2, 3 CH), 1.68 1.60 (m, 4H, CH 2 ), 2.97 2.91 (m, 4H, CH 2 ), 6.48 (dd, 1H, CH, 4 J H,H = 1.5 Hz, 3 J H,H = 2.9 Hz), 6.78 6.76 (m, 1H, CH), 7.18 (dd, 1H, CH, 4 J H,H = 1.5 Hz, 4 J H,H = 2.0 Hz). 13 C MR (101 MHz, CDCl 3 ): δ 11.6, 17.7, 23.8, 25.3, 47.0, 110.3, 120.6, 125.6, 128.2. HRMS-ESI: calcd. for C 18 H 34 2 2 SSiH + S15

([M+H] + ), 371.2183; found 371.2178. Calcd. for C 18 H 34 2 2 SSia + ([M+a] + ), 393.2002; found 393.1994. 5-(Piperidin-1-ylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (17) Method B. btained from 5-bromo-1H-pyrrolo[2,3-b]pyridine (9) (96% pure, 102 mg, 0.5 mmol). For the bromine-lithium exchange 1.8 equivalents t-buli (1.56M, 0.58 ml) were used. Column chromatographic purification (Si 2, CH/EtAc, 1:1) yielded a mixture of the desired product and several byproducts which could not be separated. HRMS-ESI: calcd. for C 12 H 15 3 2 Sa + ([M+a] + ), 288.0778; found 288.0787. GC-MS: m/z (%), 265 (30) [M + ], 181 (16) [C 7 H 5 2 2 S + ], 117 (39) [C 7 H 5 + 2 ], 84 (100) [C 5 H + 10 ]. S16

3. MR Spectroscopy 5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1) 1 H MR Br Si 13 C MR S17

4-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3) 1 H MR Br Si 1.00 1.00 0.98 0.98 3.06 17.99 13 C MR 153.64 142.58 131.80 124.19 123.99 119.23 103.11 77.58 77.16 76.74 18.22 12.35 S18

3-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (4) 1 H MR Br Si 1.00 1.00 1.02 1.03 3.20 18.36 13 C MR 152.56 143.62 129.83 126.72 121.66 116.71 91.32 77.16 18.22 12.40 S19

5-Bromo-1-propyl-1H-pyrrolo[2,3-b]pyridine (5) 1 H MR 1.00 1.02 1.03 1.03 2.12 2.14 3.24 13 C MR 145.90 143.16 130.68 129.52 122.13 111.44 98.87 77.16 46.49 23.69 11.42 S20

1-(Triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine-5-sulfonyl chloride (2) 1 H MR Si Cl S 0.97 0.97 1.00 1.01 3.24 18.47 13 C MR 155.91 140.82 135.28 133.76 127.70 121.64 105.06 77.16 18.12 12.25 S21

5-(Piperidin-1-ylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (10) 1 H MR S Si 0.97 1.00 1.00 0.98 4.09 3.21 4.43 2.65 18.33 13 C MR 155.28 141.57 133.81 128.13 124.78 121.56 104.20 77.16 47.07 25.28 23.60 18.17 12.28 S22

4-(Piperidin-1-ylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (11) 1 H MR S Si 1.00 1.00 1.03 0.98 4.18 3.40 4.68 2.65 18.73 13 C MR 155.44 141.80 134.95 134.09 118.91 114.71 103.67 77.16 47.01 25.37 23.56 18.21 12.32 S23

3-(Piperidin-1-ylsulfonyl)-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (12) 1 H MR S Si 1.00 1.02 1.00 1.02 4.04 3.27 4.42 2.27 18.28 13 C MR 153.27 144.30 135.94 128.38 119.02 118.03 112.11 77.16 46.89 25.27 23.62 18.09 12.20 S24

5-(Piperidin-1-ylsulfonyl)-1-propyl-1H-pyrrolo[2,3-b]pyridine (13) 1 H MR S 0.98 0.99 1.00 1.01 2.13 4.22 2.38 4.40 2.37 3.21 13 C MR 148.64 141.90 130.68 128.95 124.34 119.63 100.96 77.16 47.02 46.67 25.20 23.67 23.53 11.41 S25

3-Methoxy-5-(piperidin-1-ylsulfonyl)pyridine (14) 1 H MR S 1.00 1.03 1.00 3.11 4.13 4.37 2.29 13 C MR 155.62 142.04 140.20 133.50 118.50 77.16 56.11 46.93 25.18 23.46 S26

1-((2,3,4-Trimethoxyphenyl)sulfonyl)piperidine (15) 1 H MR S 1.00 1.02 3.05 3.05 3.19 4.07 4.33 2.24 13 C MR 157.54 151.95 143.07 126.40 124.36 106.44 77.16 61.76 61.01 56.23 46.84 25.66 23.88 S27

1-((1-(Triisopropylsilyl)-1H-pyrrol-3-yl)sulfonyl)piperidine (16) 1 H MR S TIPS 1.00 0.99 0.98 4.15 4.33 5.83 18.53 13 C MR 128.20 125.63 120.62 110.34 77.16 47.04 25.29 23.81 17.75 11.65 S28

Long-term measurement of the stability of 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo [2,3-b]pyridine (1) after bromine-lithium exchange 1 H MR Si S29

4. GC-MS General remark: 2,6-bis(1,1-dimethylethyl)-4-methylphenol (BHT) often appears at 9.96 min. 5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (1) 1.0 equivalent t-buli Si Br Si 2.0 equivalents t-buli S30

4-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (3) 1.0 equivalent t-buli Si 2.0 equivalents t-buli S31

3-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (4) 1.0 equivalent t-buli Si 2.0 equivalents t-buli S32

5-Bromo-1-propyl-1H-pyrrolo[2,3-b]pyridine (5) 1.0 equivalents t-buli Br 2.0 equivalents t-buli S33

3-Bromo-5-methoxypyridine (6) 1.0 equivalent t-buli Br 1.2 equivalents t-buli 1.4 equivalents t-buli S34

1.6 equivalents t-buli 2.0 equivalents t-buli S35

1-Bromo-2,3,4-trimethoxybenzene (7) 1.0 equivalent t-buli Br 1.2 equivalents t-buli 1.4 equivalents t-buli S36

2.0 equivalents t-buli S37

3-Bromo-1-(triisopropylsilyl)-1H-pyrrole (8) 1.0 equivalent t-buli Si Br Si 1.2 equivalents t-buli 2.0 equivalents t-buli S38

5-Bromo-1H-pyrrolo[2,3-b]pyridine (9) 1.0 equivalent t-buli H Br H H 1.2 equivalents t-buli 1.4 equivalents t-buli S39

1.6 equivalents t-buli 1.8 equivalents t-buli 2.0 equivalents t-buli S40