First Selective CYP11B1 Inhibitors for the Treatment of Cortisol

Oct 22, 2010 - Outgoing from an etomidate-based design concept, we succeeded in the development of a series of highly active and selective inhibitors ...
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Discovery of the first selective steroid-11β-hydroxylase (CYP11B1) inhibitors for the treatment of cortisol dependent diseases

Ulrike E. Hille, Christina Zimmer, Carsten A. Vock and Rolf W. Hartmann Pharmaceutical and Medicinal Chemistry, Saarland University & Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2 3, D-66123 Saarbrücken, Germany

Supporting Information

Experimental Procedures Biology Inhibition of CYP11B1 and CYP11B2 V79MZh11B1 or V79MZh11B2 cells expressing CYP11B1 or CYP11B2 were used and our assay procedure with [1,2-3H]-11-deoxycorticosterone as substrate was applied. Product formation was monitored by HPLC using a radioflow detector.33,34 CYP17 preparation and assay As source of human CYP17, our E. coli system35 coexpressing human CYP17 and NADPHP450 reductase was used. The assay was performed as previously described10 using unlabeled progesterone as substrate and applying HPLC with UV-detection for separation. CYP19 preparation and assay As source of human CYP19, microsomal preparations of human placenta were used. The assay was performed using the 3H2O-method as described1 and [1β-3H]androstenedione as substrate. Chemistry General Experimental 1

H NMR and 13C spectra were recorded on a Bruker DRX-500 instrument. Chemical shifts are

given in parts per million (ppm) and spectra are obtained as DMSO-d6 or CDCl3 solutions (reported in ppm), using chloroform as the reference standard (7.26 ppm) or DMSO-d6 (2.50 ppm). The following abbreviations are used to denote signal multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, mc = symmetric multiplet and br = broadened. All coupling constants (J) are given in Hertz (Hz). Mass spectra (LC/MS) were measured on a TSQ Quantum (Thermo Electron Corporation) instrument with a RP18 100-3 column (Macherey Nagel) and with water/acetonitrile mixtures as eluents. The purity of all compounds was ≥95%. Reagents were used as obtained from commercial suppliers without further purification. Yields refer to purified products and are not optimized. Solvents were 2

distilled before use. Dry solvents were obtained by distillation from appropriate drying reagents and stored over molecular sieves. Flash chromatography was performed on silica gel 40 (35/40−63/70 μM) with petroleum ether/ethyl acetate mixtures as eluents, and the reaction progress was determined by thin-layer chromatography analyses on Alugram SIL G/UV254 (Macherey Nagel). Visualization was accomplished with UV light and KMnO4 solution. Method A: SN-Reaction K2CO3 (5 eq.), imidazole (4 eq.) or benzimidazole (2 eq.) and the corresponding benzyl chloride or bromide were suspended in DMF (1 mL / mmol) or acetonitrile (1mL / mmol). The resulting mixture was heated to 120°C for 2 h. After cooling, water (50 mL) was added, and the aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4 and evaporated in vacuo. The crude product was purified by column chromatography using SiO2.

Method B: Suzuki-Coupling The corresponding benzene derivative and the boronic acid were dissolved in toluene (20 mL), ethanol (20 mL) and aq. Na2CO3 (2.0 M, 5.0 mL). The mixture was deoxygenated under reduced pressure and flushed with N2. After having repeated this cycle three times, Pd(PPh3)4 (5 mol%) was added, and the resulting suspension was heated under reflux for 4 h. After cooling, the phases were separated and the water phase was extracted two times with EtOAc. The combined organic extracts were dried over Na2SO4, and concentrated under reduced pressure. The purification was performed by flash chromatography using SiO2. Method C: Reduction with LiAlH4 To a stirred ice-cooled suspension of lithium aluminium hydride in tetrahydrofurane (1.5 mL / mmol), the corresponding acid was added dropwise in tetrahydrofurane (2 mL / mmol). The hydride mixture was stirred at room temperature overnight and excess LiAlH4 was decomposed by slow addition of water. A standard alkaline workup and flash chromatography 3

using SiO2 led to the desired alcohol. Method D: Reduction with NaBH4 To an ice-cooled solution of the corresponding aldehyde in THF (5 mL / mmol) was added NaBH4 in methanol (5 mL / mmol). The resulting mixture was stirred at rt for 1 hour. After complete conversion, the solvent was distilled off under reduced pressure. Then water was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The desired product was purified by chromatography on silica gel. Method E: Synthesis of Tosylates To a solution of the corresponding alcohol and pyridine in dry DCM (10 mL / mmol), trifluoromethanesulfonic anhydride was carefully added over 1 min. at 0°C. The reaction mixture was stirred at room temperature for 3 h. Afterwards, excess trifluoromethanesulfonic anhydride was neutralized with Na2CO3, and the crude product was washed two times with water. The organic phase was dried over Na2SO4 and concentrated. Purification of the residue was performed by flash chromatography using SiO2. Method F: CDI reaction To a solution of the corresponding alcohol (1 eq) in NMP or acetonitrile (10 mL / mmol) was added CDI (5 eq). Then the solution was heated to reflux for 4 to 18 h. After cooling to ambient temperature, it was diluted with water (30 mL) and extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with brine, dried over MgSO4 and evaporated under reduced pressure. Then the desired product was purified by chromatography on silica gel. 1-(5-Phenyl-furan-2-ylmethyl)-1H-imidazole (34). Synthesized using compound 34a (137 mg, 0.80 mmol) and CDI (258 mg, 1.59 mmol) according to Method F. Yellow solid. Yield: 87 mg, 48 %; 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.14 (s, 2H), 6.38 (d, J = 3.5 Hz, 1H), 6.59 (d, J = 3.5 Hz, 1H), 7.01 (brs, 1H), 7.08 (brs, 1H), 7.27 – 7.29 (m, 1H), 7.38 (t, 4

J = 7.8 Hz, 2H), 7.59 (brs, 1H), 7.61 – 7.63 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 43.8, 105.7, 111.0, 119.0, 123.8, 127.8, 128.7, 129.7, 130.2, 137.1, 148.3, 154.7; MS (ESI): m/z = 224.9 [M+H] +. 1-(5-Phenyl-thiophen-2-ylmethyl)-1H-imidazole (35). Synthesized using compound 35a (190 mg, 1.00 mmol) and CDI (324 mg, 2.00 mmol) according to Method F. Yield: 127 g, 53 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.27 (s, 2H), 6.94 (d, J = 3.7 Hz, 1H), 6.99 (brs, 1H), 7.09 (brs, 1H), 7.15 (d, J = 3.7 Hz, 1H), 7.27 – 7.31 (m, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.53 – 7.55 (m, 2H), 7.59 (brs, 1H);

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C NMR (CDCl3, 125 MHz): δC (ppm) = 45.77,

118.9, 122.9, 125.8, 127.8, 127.9, 129.0, 129.9, 133.8, 137.0, 139.0, 142.2; MS (ESI): m/z = 241.1 [M+H] +. 1-((4-Phenylthiophen-2-yl)methyl)-1H-imidazole (36). Synthesized using 36a (0.19 g, 1.00 mmol) and CDI (0.24 g, 1.50 mmol) according to Method F. Light brown solid. Yield: 0.09 g, 38 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.29 (s, 2H), 7.00 (t, J = 1.3 Hz, 1H), 7.10 (bs, 1H), 7.24-7.25 (m, 1H), 7.30 (tt, J = 1.3, 7.5 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.39 (dd, J = 7.5, 7.8 Hz, 2H), 7.53 (dd, J = 1.3, 7.8 Hz, 2H), 7.60 (s, 1H);

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C NMR (CDCl3,

125 MHz): δC (ppm) = 45.7, 118.9, 120.8, 126.0, 126.3, 127.5, 128.9, 130.0, 135.2, 137.0, 139.2, 142.4; MS (ESI): m/z = 241.1 [M+H] +. 1-Benzyl-1H-imidazole (1). Product was commercially available (98 % purity, Acros). 1-(4-Chloro-benzyl)-1H-imidazole (2). Synthesized from 1-bromomethyl-4-chloro-benzene (1.03 g, 5.00 mmol), imidazole (1.36 g, 20.0 mmol) and K2CO3 (3.46 g, 25.0 mmol) in DMF according to Method A. Yellow oil. Yield: 740 mg, 3.84 mmol, 77 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.08 (s, 2H), 6.87 (t, J = 1.3 Hz, 1H), 7.07 (d, J = 8.8 Hz, 2H), 7.09 (t, J = 1.3 Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H), 7.53 (brs, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 50.07, 119.1, 128.6, 129.2, 130.1, 134.2, 134.7, 137.4; MS (ESI): m/z = 193.6 [M+H] +. 1-(2-Methyl-benzyl)-1H-imidazole · HCl (3). Synthesized from 1-chloromethyl-3-methyl5

benzene (0.66 mL, 4.99 mmol), imidazole (1.36 g, 20.0 mmol) and K2CO3 (3.46 g, 25.0 mmol) in DMF according to Method A. After evaporation of the solvent, the oily residue was taken up in EtOAc / hexane (1:1), and a solution of HCl in Et2O (2M, 3.0 mL, 6.0 mmol, 1.20 eq.) was added dropwise. A white precipitate formed, which was filtered off with suction, washed with EtOAc (4 × 10 mL) and dried in vacuo, affording a white solid (146 mg, 0.700 mmol, 14 %). 1H NMR (DMSO-d6, 500 MHz): δH (ppm) = 2.30 (s, 3H), 5.48 (brs, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.21 – 7.32 (m, 3H), 7.69 (t, J = 1.6 Hz, 1H), 7.72 (t, J = 1.6 Hz, 1H), 9.26 (t, J = 1.6 Hz, 1H), 14.98 (brs, 1H). 13C NMR (CDCl3, 125 MHz): δC (ppm) = 18.55, 49.78, 120.2, 122.2, 126.5, 128.4, 128.7, 130.6, 133.0, 135.6, 136.3; MS (ESI): m/z = 208.7 [M · HCl +H] +. 1-(3-Methyl-benzyl)-1H-imidazole (4). Synthesized from 1-chloromethyl-3-methyl-benzene (422 mg, 3.00 mmol), imidazole (817 mg, 12.0 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. Pale yellow solid. Yield: 496 mg, 96 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.26 (s, 3H), 4.97 (s, 2H), 6.82 (brs, 1H), 6.88 – 6.90 (m, 2H), 7.02 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.46 (s, 1H);

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C NMR (CDCl3,

125 MHz): δC (ppm) = 20.97, 50.36, 119.0, 124.0, 127.6, 128.5, 128.6, 129.3, 135.9, 137.1, 138.4; MS (ESI): m/z = 173.3 [M+H] +. 1-(4-Methyl-benzyl)-1H-imidazole (5). Synthesized from 1-chloromethyl-4-methyl-benzene (422 mg, 3.00 mmol), imidazole (817 mg, 12.0 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. Pale yellow solid. Yield: 295 mg, 1.71 mmol, 57 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.33 (s, 3H), 5.05 (s, 2H), 6.87 (brs, 1H), 7.04 (d, J = 7.9 Hz, 2H), 7.06 (s, 1H), 7.14 (d, J = 7.9 Hz, 2H), 7.51 (s, 1H).

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C NMR (CDCl3, 125 MHz): δC

(ppm) = 21.01, 50.53, 119.1, 127.3, 129.55, 129.58, 133.0, 137.3, 138.0; MS (ESI): m/z = 173.5 [M+H] +.

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1-(3,5-Dimethyl-benzyl)-1H-imidazole (6). Synthesized from 1-bromomethyl-3,5-dimethylbenzene (597 mg, 3.00 mmol), imidazole (817 mg, 12.0 mmol) and K2CO3 (2.07 g, 15.0 mmol) according to Method A. Pale yellow solid. Yield: 450 mg, 2.42 mmol, 81 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.46 (s, 6H), 5.17 (s, 2H), 6.95 (s, 2H), 7.08 (s, 1H), 7.13 (s, 1H), 7.26 (s, 1H), 7.70 (s, 1H);

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C NMR (CDCl3, 125 MHz): δC (ppm) = 20.69,

50.14, 118.8, 124.6, 129.1, 129.3, 135.7, 136.9, 138.0; MS (ESI): m/z = 187.2 [M+H] +. 1-(2,4,6-Trimethyl-benzyl)-1H-imidazole (7). Synthesized from 2-chloromethyl-1,3,5trimethyl-benzene (506 mg, 3.00 mmol), imidazole (817 mg, 12.0 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. Pale yellow solid. Yield: 322 mg, 1.61 mmol, 54 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.26 (s, 6H), 2.29 (s, 3H), 5.10 (s, 2H), 6.75 (brs, 1H), 6.91 (s, 2H), 7.02 (brs, 1H), 7.33 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 19.47, 20.94, 44.81, 118.5, 128.1, 129.2, 129.5, 136.7, 137.6, 138.5; MS (ESI): m/z = 201.2 [M+H] +. 1-Pentamethylphenylmethyl-1H-imidazole (8). Synthesized from 1-chloromethyl-2,3,4,5,6pentamethyl-benzene (984 mg, 5.00 mmol), imidazole (1.36 mg, 20.0 mmol) and K2CO3 (3.46 g, 25.0 mmol) in DMF according to Method A. White crystalline solid. Yield: 1.00 g, 4.37 mmol, 87 %. 1H NMR (CDCl3, 500 MHz): δH (ppm): 2.23 (s, 6H), 2.24 (s, 6H), 2.27 (s, 3H), 5.19 (s, 2H), 6.79 (t, J = 1.3 Hz, 1H), 7.02 (t, J = 1.3 Hz, 1H), 7.32 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 16.38, 16.79, 17.08, 46.06, 118.6, 128.1, 129.2, 133.2, 133.3, 135.9, 136.6; MS (ESI): m/z = 229.2 [M+H] +. 1-Biphenyl-2-ylmethyl-1H-imidazole (9). Synthesized from 2-bromomethyl-biphenyl (1.24 g, 5.00 mmol), imidazole (1.36 g, 20.0 mmol) and K2CO3 (3.46 g, 25.0 mmol) in DMF according to Method A. Yellow oil. Yield: 1.12 g, 4.78 mmol, 96 %. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.01 (s, 2H), 6.68 (s, 1H), 6.98 (s, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.18 – 7.21

7

(m, 3 H), 7.27 (d, J = 7.5 Hz, 1H), 7.32 – 7.42 (m, 5H);

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C NMR (CDCl3, 125 MHz): δC

(ppm) = 48.56, 118.9, 127.5, 127.9, 128.1, 128.3, 128.4, 128.7, 129.3, 130.3, 133.3, 137.1, 139.9, 141.8; MS (ESI): m/z = 235.10 [M+H] +. 1-Biphenyl-3-ylmethyl-1H-imidazole (10). Synthesized from 3-bromomethyl-biphenyl (500 mg, 2.02 mmol), imidazole (551 mg, 8.09 mmol) and K2CO3 (1.40 g, 10.1 mmol) in DMF according to Method A. Yield: 377 mg, 1.61 mmol, 80 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.22 (s, 2H), 6.96 (t, J = 1.3 Hz, 1H), 7.13 (t, J = 1.3 Hz, 1H), 7.13 – 7.16 (m, 1H), 7.34 – 7.38 (m, 2H), 7.42 – 7.46 (m, 3H), 7.53 – 7.57 (m, 3H), 7.79 (s, 1H);

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C NMR

(CDCl3, 125 MHz): δC (ppm) = 51.09, 119.4, 126.1, 126.2, 127.1, 127.2, 127.7, 128.9, 129.5, 136.3, 137.2, 140.3, 142.2; MS (ESI): m/z = 235.13 [M+H] +. 1-Biphenyl-4-ylmethyl-1H-imidazole (11). Synthesized from 4-bromomethyl-biphenyl (500 mg, 2.02 mmol), imidazole (551 mg, 8.09 mmol) and K2CO3 (1.40 g, 10.1 mmol)in DMF according to Method A. White solid. Yield: 450 mg, 1.92 mmol, 95 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.16 (s, 2H), 6.94 (t, J = 1.3 Hz, 1H), 7.11 (t, J = 1.3 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.34 – 7.38 (m, 1H), 7.42 – 7.46 (m, 2H), 7.55 – 7.59 (m, 5H);

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C NMR

(CDCl3, 125 MHz): δC (ppm) = 50.50, 119.3, 127.1, 127.6, 127.68, 127.71, 128.8, 129.9, 135.1, 137.5, 140.3, 141.3; MS (ESI): m/z = 235.12 [M+H] +. 5'-Methyl-[1,1';3',1'']terphenyl (12b). Synthesized from 3,5-dibromotoluene (1.00 g, 4.00 mmol), benzene boronic acid (1.46 g, 12.0 mmol) and Na2CO3 (1.70 g, 16.0 mmol) according to Method B. Yellow solid. Yield: 942 mg, 3.86 mmol, 96 %. 1H NMR (CDCl3, 500 MHz): δH (ppm): 2.51 (s, 3H), 7.37 – 7.40 (m, 2H), 7.42 – 7.43 (m, 2H), 7.46 – 7.49 (m, 4H), 7.64 – 7.68 (m, 5H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 21.59, 123.4, 127.0, 127.26, 127.30, 128.7, 138.8, 141.3, 141.8. The compound was directly used in the next step without further purification.

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5'-Bromomethyl-[1,1';3',1'']terphenyl (12a). 12b (942 mg, 3.86 mmol) was dissolved in 20 mL of dry carbon tetrachloride. To this solution was added N-bromsuccinimide (NBS) (755 mg, 4.24 mmol) and benzoyl peroxide (47 mg, 0.19 mmol) and the mixture was refluxed over night. After cooling, the succinimide was removed by filtration and the filtrate was concentrated under vacuum. The crude product was further purified by flash column chromatography on silica gel using a mixture of petroleum ether / EtOAc (95:5) as eluent. Yellow solid. Yield: 540 mg, 1.67 mmol (43 %); 1H NMR (CDCl3, 500 MHz): δH (ppm): 4.64 (s, 2H), 7.42 – 7.45 (m, 2H), 7.49 – 7.53 (m, 4H), 7.64 (d, J = 1.9 Hz, 2H), 7.68 – 7.71 (m, 4H), 7.78 (t, J = 1.9 Hz);

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C NMR (CDCl3, 125 MHz): δC (ppm) = 33.41, 126.2, 126.7,

127.2, 127.7, 128.8, 138.7, 140.5, 142.4. The compound was directly used in the next step without further purification. 1-[1,1';3',1'']Terphenyl-5'-ylmethyl-1H-imidazole (12). Synthesized from 12a (167 mg, 0.51 mmol), imidazole (141 mg, 2.06 mmol) and K2CO3 (357 mg, 2.58 mmol) in DMF according to Method A. Pale yellow solid. Yield: 120 mg, 0.38 mmol, 75 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.23 (s, 2H), 6.99 (s, 1H), 7.13 (s, 1H), 7.336 – 7.339 (m, 2H), 7.37 – 7.40 (m, 2H), 7.44 – 7.48 (m, 4H), 7.58 – 7.60 (m, 4H), 7.63 (s, 1H), 7.758 – 7.761 (m, 1H).

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C NMR (CDCl3, 125 MHz): δC (ppm) = 50.80, 119.3, 124.8, 126.0, 127.1, 127.8,

128.9, 129.9, 137.2, 137.5, 140.3, 142.6; MS (ESI): m/z = 311.2 [M+H] +. 1-Benzyl-1H-benzoimidazole (13). Synthesized from benzyl bromide (0.24 mL, 2.02 mmol), benzimidazole (4736 g, 4.00 mmol) and K2CO3 (1.38 g, 9.98 mmol) in DMF according to Method A. White solid. Yield: 246 mg, 1.18 mmol, 58 %.1H NMR (500 MHz, CDCl3): δH (ppm) = 5.34 (brs, 2H), 7.18 (mc, 2H), 7.22 – 7.36 (m, 6H), 7.82 (mc, 1H), 7.93 (brs, 1H). 13C NMR (125 MHz, CDCl3): δC (ppm) = 48.81, 110.0, 120.4, 122.2, 123.0, 127.1, 128.2, 129.0, 133.9, 135.5, 143.2, 144.0; MS (ESI): m/z = 208.3 [M+H] +.

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1-(4-Chloro-benzyl)-1H-benzoimidazole (14). Synthesized from 1-bromomethyl-4-chlorobenzene (440 mg, 2.14 mmol), benzimidazole (473 mg, 4.00 mmol) and K2CO3 (1.38 g, 9.98 mmol) in DMF according to Method A. Yield: 328 mg, 1.35 mmol, 63 %. 1H NMR (500 MHz, CDCl3): δH (ppm) = 5.33 (brs, 2H), 7.11 (mc, 2H), 7.23 – 7.30 (m, 3H), 7.31 (mc, 2H), 7.84 (mc, 1H), 7.94 (brs, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 48.19, 109.9, 120.6, 122.4, 123.2, 128.3, 129.2, 133.7, 134.0, 134.2, 143.0, 144.0; MS (ESI): m/z = 243.0 [M+H] +. 1-(2-Methyl-benzyl)-1H-benzoimidazole

hydrochloride

(15).

Synthesized

from

1-

chloromethyl-2-methyl-benzene (0.66 mL, 4.99 mmol), benzimidazole (2.36 g, 20.0 mmol) and K2CO3 (3.46 g, 25.0 mmol) in DMF according to Method A. White solid. Yield: 1.16 g, 4.48 mmol, 90 %.1H NMR (500 MHz, DMSO-d6): δH (ppm) = 2.35 (s, 3H), 5.78 (brs, 2H), 7.02 (d, J = 7.6 Hz, 1H), 7.18 (mc, 1H), 7.25 – 7.30 (m, 2H), 7.56 (td, J = 7.5 Hz, 1.2 Hz, 1H), 7.59 (td, J = 7.5 Hz, 1.3 Hz, 1H), 7.78 (dd, J = 1.3 Hz, 7.5 Hz, 1H), 7.91 (dd, J = 7.5 Hz, 1.2 Hz, 1H), 9.64 (brs, 1H).

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C NMR (125 MHz, DMSO-d6): δC (ppm) = 18.74, 47.94, 113.3,

115.4, 125.9, 126.2, 126.4, 127.6, 128.5, 130.7, 131.3, 131.9, 132.4, 136.2, 142.1; MS (ESI): m/z = 223.1 [M+H] +. 1-(3-Methyl-benzyl)-1H-benzoimidazole (16). Synthesized from 1-chloromethyl-3-methylbenzene (422 mg, 3.00 mmol), benzimidazole (709 mg, 6.00 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. White solid. Yield: 510 mg, 2.29 mmol, 76 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.27 (s, 3H), 5.22 (s, 2H), 6.94 (d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.21 – 7.28 (m, 3H), 7.82 – 7.84 (m, 1H), 7.89 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 21.14, 48.54, 109.9, 120.2, 122.0, 122.8, 124.0, 127.6, 128.8, 133.8, 135.3, 138.6, 143.0, 143.8; MS (ESI): m/z = 223.0 [M+H] +. 1-(4-Methyl-benzyl)-1H-benzoimidazole (17). Synthesized from 1-chloromethyl-4-methylbenzene (422 mg, 3.00 mmol), benzimidazole (709 mg, 6.00 mmol) and K2CO3 (2.07 g, 15.0

10

mmol) in DMF according to Method A. White solid. Yield: 540 mg, 2.43 mmol, 81 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.33 (s, 3H), 5.27 (s, 2H), 7.07 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 7.6 Hz, 2H), 7.23 – 7.30 (m, 3H), 7.82 – 7.84 (m, 1H), 7.91 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 20.98, 48.52, 109.9, 120.3, 122.1, 122.9, 127.0, 129.6, 132.3, 133.9, 138.0, 143.1, 143.9; MS (ESI): m/z = 223.0 [M+H] +. 1-(3,5-Dimethyl-benzyl)-1H-benzoimidazole (18). Synthesized from 1-bromomethyl-3,5dimethyl-benzene (597 mg, 3.00 mmol), benzimidazole (709 mg, 6.00 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. Pale orange solid. Yield: 686 mg, 2.90 mmol, 97 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.27 (s, 6H), 5.27 (s, 2H), 6.81 (s, 2), 6.94 (s, 1H), 7.24 – 7.33 (m, 3H), 7.82 – 7.84 (m, 1H), 7.93 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 21.20, 48.76, 110.0, 120.4, 122.1, 123.0, 124.9, 129.9, 134.0, 135.3, 138.7, 143.2, 144.0; MS (ESI): m/z = 237.0 [M+H] +. 1-(2,4,6-Trimethyl-benzyl)-1H-benzoimidazole (19). Synthesized from 2-chloromethyl1,3,5-trimethyl-benzene (506 mg, 3.00 mmol), benzimidazole (709 mg, 6.00 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. Yellowish solid. Yield: 616 mg, 2.46 mmol, 82 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.25 (s, 6H), 2.34 (s, 3H), 5.25 (s, 2H), 6.97 (brs, 2H), 7.29 – 7.35 (m, 2H), 7.43 (s, 1H), 7.45 – 7.47 (m, 1H), 7.81 – 7.83 (m, 1H);

13

C NMR (CDCl3, 125 MHz): δC (ppm) = 19.54, 21.00, 43.09, 109.5, 120.4, 122.2,

122.8, 127.1, 129.6, 134.2, 137.8, 138.8, 141.7, 144.1; MS (ESI): m/z = 251.0 [M+H] +. 1-Pentamethylphenylmethyl-1H-benzoimidazole (20). Synthesized from 1-chloromethyl2,3,4,5,6-pentamethyl-benzene (590 mg, 3.00 mmol), benzimidazole (709 mg, 6.00 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. White solid. Yield: 716 mg, 2.58 mmol, 86 %.1H NMR (CDCl3, 500 MHz): δH (ppm): 2.21 (s, 6H), 2.27 (s, 6H), 2.32 (s, 3H), 5.31 (s, 2H), 7.30 – 7.37 (m, 2H), 7.40 (s, 1H), 7.52 – 7.54 (m, 1H), 7.82 – 7.84 (m, 1H);

11

13

C NMR (CDCl3, 125 MHz): δC (ppm) = 16.49, 16.83, 17.12, 44.31, 109.5, 120.4, 122.2,

122.7, 133.4, 133.5, 134.1, 136.2, 141.9, 144.2; MS (ESI): m/z = 279.21 [M+H] +. 1-Biphenyl-2-ylmethyl-1H-benzoimidazole

(21).

Synthesized

from

2-bromomethyl-

biphenyl (741 mg, 3.00 mmol), benzimidazole (710 mg, 6.00 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. White solid. Yield: 647 mg, 2.28 mmol, 76 %. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.26 (s, 2H), 7.05 – 7.10 (m, 2H), 7.15 (dt, J = 0.9 Hz, J = 7.5 Hz, 1H), 7.19 – 7.30 (m, 5H), 7.33 – 7.42 (m, 4H), 7.53 (s, 1H), 7.74 (td, J = 0.9 Hz, J = 7.9 Hz, 1H);

13

C NMR (CDCl3, 125 MHz): δC (ppm) = 46.94, 109.9, 120.3, 122.0, 122.8,

127.7, 128.0, 128.1, 128.2, 128.6, 128.8, 130.5, 132.7, 133.8, 140.1, 141.8, 143.1, 143.8. MS (ESI): m/z = 285.01 [M+H] +. 1-Biphenyl-3-ylmethyl-1H-benzoimidazole

(22).

Synthesized

from

3-bromomethyl-

biphenyl (500 mg, 2.02 mmol), benzimidazole (479 mg, 4.05 mmol) and K2CO3 (1.40 g, 10.1 mmol) in DMF according to Method A. Yield: 508 mg, 1.78 mmol, 88 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.26 (s, 2H), 7.00 (qd, J = 0.9 Hz, 7.9 Hz, 1H), 7.10 – 7.16 (m, 2H), 7.18 – 7.22 (m, 2H), 7.24 – 7.29 (m, 4H), 7.36 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 7.9 Hz, 1H), 7.69 (td, J = 1.3 Hz, 7.9 Hz, 1H), 7.84 (s, 1H);

13

C NMR (CDCl3, 125 MHz): δC (ppm) =

49.21, 110.2, 119.9, 123.0, 126.01, 126.04, 127.1, 127.3, 127.7, 128.8, 129.6, 133.5, 135.5, 140.3, 142.3, 142.7 ; MS (ESI): m/z = 285.1 [M+H] +. 1-Biphenyl-4-ylmethyl-1H-benzoimidazole

(23).

Synthesized

from

4-bromomethyl-

biphenyl (500 mg, 2.02 mmol), benzimidazole (479 mg, 4.05 mmol) and K2CO3 (1.40 g, 10.1 mmol) in DMF according to Method A. White solid. Yield: 540 mg, 1.90 mmol, 94 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.46 (s, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.31 – 7.40 (m, 4H), 7.41 – 7.45 (m, 2H), 7.54 – 7.58 (m, 4H), 7.87 (td, J = 1.3 Hz, 8.2 Hz, 1H), 8.31 (s, 1H); 13

C NMR (CDCl3, 125 MHz): δC (ppm) = 48.93, 110.4, 119.8, 123.0, 123.7, 127.1, 127.6,

12

127.7, 127.8, 128.8, 133.5, 133.9, 140.2, 141.5, 142.0, 142.7; MS (ESI): m/z = 285.10 [M+H] +. 1-[1,1';3',1'']Terphenyl-5'-ylmethyl-1H-benzoimidazole (24). Synthesized from 12a (354 mg, 1.10 mmol), benzimidazole (260 mg, 2.2 mmol) and K2CO3 (760 mg, 5.50 mmol) in DMF according to Method A. White solid. Yield: 290 mg, 0.80 mmol 73 %. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.25 (s, 2H), 7.05 – 7.11 (m, 2H), 7.14 – 7.18 (m, 5H), 7.21 – 7.24 (m, 4H), 7.33 – 7.36 (m, 4H), 7.54 (t, J = 1.6 Hz, 1H), 7.64 – 7.65 (m, 1H), 7.83 (s, 1H); 13

C NMR (CDCl3, 125 MHz): δC (ppm) = 48.91, 110.0, 120.5, 122.4, 123.2, 124.7, 126.1,

127.2, 127.8, 128.8, 133.9, 136.5, 140.3, 142.7, 143.1, 143.9; MS (ESI): m/z = 361.02 [M+H] +. Toluene-4-sulfonic acid adamantan-1-ylmethyl ester (25a). Synthesized from adamantan1-yl-methanol (1.00 g, 6.02 mmol) and 4-Methyl-benzenesulfonyl chloride (1.26 g, 6.63 mmol) according to Method E. Yield: 1.85 g, 5.77 mmol, 96 %. The compound was directly used in the next step without further purification. 1-Adamantan-1-ylmethyl-1H-imidazole (25). Synthesized from 25a (961 mg, 3.00 mmol), imidazole (817 mg, 12.0 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to Method A. White solid. Yield: 250 mg, 1.16 mmol, 39 %. 1H NMR (CDCl3, 500 MHz): δH (ppm): 1.45 (d, J = 2.5 Hz, 6H), 1.56 (d, J = 12.3 Hz, 3H), 1.68 (d, J = 12.3 Hz, 3H), 1.97 (brs, 3H), 3.55 (s, 2H), 6.79 (brs, 1H), 7.00 (brs, 1H), 7.34 (s, 1H);

13

C NMR (CDCl3, 125 MHz): δC

(ppm) = 28.03, 34.01, 36.52, 40.24, 59.54, 120.8, 128.4, 138.2; MS (ESI): m/z = 217.1 [M+H] +

.

1-Adamantan-1-ylmethyl-1H-benzoimidazole (26). Synthesized from 25a (891 mg, 2.78 mmol), benzimidazole (658 mg, 5.56 mmol) and K2CO3 (1.92 g, 13.9 mmol) in DMF according to Method A. White solid. Yield: 375 mg, 1.41 mmol, 51 %. 1H NMR (CDCl3, 500 13

MHz): δH (ppm): 1.56 – 1.59 (m, 9H), 1.69 (d, J = 12.3 Hz, 3H), 1.99 (brs, 3H), 3.82 (s, 2H), 7.24 – 7.30 (m, 2H), 7.39 – 7.41 (m, 1H), 7.79 – 7.81 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 28.09, 35.36, 36.52, 40.73, 57.09, 110.4, 120.1, 121.7, 122.7, 135.2, 143.3, 144.3; MS (ESI): m/z = 267.21 [M+H] +. 1-Trityl-1H-imidazole (27). Synthesized from trityl chloride (1.39 g, 5.00 mmol), imidazole 1.36 g, 20.0 mmol) and K2CO3 (3.46 g, 25.0 mmol) in DMF according to Method A. White solid. Yield: 1.10 g, 3.54 mmol, 71 %. 1H NMR (CDCl3, 500 MHz): δH (ppm): 6.83 (t, J = 1.3 Hz, 1H), 7.07 (t, J = 1.3 Hz, 1H), 7.13 – 7.16 (m, 6H), 7.29 – 7.33 (m, 9H), 7.47 (t, J = 1.3 Hz, 1H);

13

C NMR (CDCl3, 125 MHz): δC (ppm) = 75.10, 121.58, 127.91, 127.93, 128.3,

129.7, 138.9, 142.4; MS (ESI): m/z = 310.83 [M+H] +. 2,2,2-Triphenyl-ethanol (28b). Synthesized from triphenyl-acetic acid (3.00 g, 10.4 mmol), LiAlH4 (395 mg, 10.4 mmol) in THF (10 mL) according to Method B. Yellow solid. Yield: 1.87 g, 6.83 mmol, 66 %. (crude product) 1H NMR (CDCl3, 500 MHz): δH (ppm) = 1.62 (t, J = 6.7 Hz, 1H), 4.69 (d, J = 6.7 Hz, 2H), 7.24 – 7.37 (m, 15H);

13

C NMR (CDCl3, 125

MHz): δC (ppm) = 58.80, 70.32, 126.6, 128.2, 129.4, 145.1. The compound was directly used in the next step without further purification. Toluene-4-sulfonic acid 2,2,2-triphenyl-ethyl ester (28a). Synthesized from 28b (1.87 g, 6.38 mmol) and 4-methyl-benzenesulfonyl chloride (1.43 g, 7.51 mmol) according to Method E. Yellow solid. Yield: 2.61 g, 6.08 mmol, 89 % (crude product). The compound was directly used in the next step without further purification. 1-(2,2,2-Triphenyl-ethyl)-1H-imidazole (28). Synthesized from 28a (1.48 g, 3.50 mmol), imidazole (940 mg, 13.8 mmol) and K2CO3 (2.42 g, 17.5 mmol) in DMF according to Method A. White solid. Yield: 624 mg, 1.92 mmol, 55 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 4.03 (s, 2H), 6.71 (d, J = 7.5 Hz, 2H), 7.03 (t, J = 1.3 Hz, 1H), 7.07 – 7.12 (m, 6H), 7.17 (dt, 14

J = 1.3 Hz, 7.5 Hz, 1H), 7.27 – 7.31 (m, 6H), 7.40 (t, J = 1.3 Hz, 1H);

13

C NMR (CDCl3,

125 MHz): δC (ppm) = 36.68, 70.70, 120.1, 127.1, 127.9, 128.0, 128.1, 128.2, 128.3, 130.9, 135.5, 138.0, 142.3; MS (ESI): m/z = 325.4 [M+H] +. 3,3,3-Triphenyl-propan-1-ol (29b). Synthesized from 3,3,3-triphenyl-propionic acid (3.00 g, 9.92 mmol), LiAlH4 (376 mg, 9.92 mmol) in THF (10 mL) according to Method B. White solid. Yield: 2.74 g, 9.50 mmol, 96 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.89 (t, J = 7.3 Hz, 2H), 3.44 (t, J = 7.3 Hz, 2H), 7.16 – 7.28 (m, 15H);

13

C NMR (CDCl3, 125 MHz):

δC (ppm) = 45.77, 53.39, 55.10, 126.0, 127.8, 128.9, 146.3; The compound was directly used in the next step without further purification. Toluene-4-sulfonic acid 3,3,3-triphenyl-propyl ester (29a). Synthesized from 29b (2.74 g, 9.50 mmol), 4-methyl-benzenesulfonyl chloride (1.99 g, 10.5 mmol) and according to Method E. Yellow solid. Yield: 1.00 g, 2.26 mmol, 24 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 2.48 (s, 3H), 3.03 (t, J = 8.2 Hz, 2H), 3.88 (t, J = 8.2 Hz, 2H), 7.18 – 7.29 (m, 15H), 7.32 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.2 Hz, 2H); The compound was directly used in the next step without further purification. 1-(3,3,3-Triphenyl-propyl)-1H-imidazole (29). Synthesized from 29a (UH134) (200 mg, 0.45 mmol), imidazole (123 mg, 1.80 mmol) and K2CO3 (311 mg, 2.25 mmol) in DMF according to Method A. White solid. Yield: 53 mg, 0.16 mmol, 35 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 3.04 – 3.08 (m, 2H), 3.70 – 3.73 (m, 2H), 6.85 (t, J = 1.3 Hz, 1H), 7.05 (t, J = 1.3 Hz, 1H), 7.21 – 7.25 (m, 3H), 7.27 – 7.33 (m, 12H), 7.36 (brs, 1H);

13

C NMR

(CDCl3, 125 MHz): δC (ppm) = 41.84, 44.30, 55.57, 118.5, 126.5, 128.3, 128.8, 129.6, 136.8, 146.0; MS (ESI): m/z = 339.0 [M+H] +. 1-Trityl-1H-benzoimidazole (30). Synthesized from trityl chloride (836 mg, 3.00 mmol), benzimidazole (709 mg, 6.00 mmol) and K2CO3 (2.07 g, 15.0 mmol) in DMF according to 15

Method A. White solid. Yield: 712 mg, 1.98 mmol, 66 %. 1H NMR (CDCl3, 500 MHz): δH (ppm): 6.48 (dt, J = 0.9 Hz, J = 8.5 Hz, 1H), 6.89 (mc, 1H), 7.14 – 7.21 (m, 7H), 7.28 – 7.33 (m, 9H), 7.78 – 7.79 (m, 1H), 7.89 (s, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 75.37, 115.3, 120.2, 122.0, 122.3, 128.0, 128.1, 129.9, 134.7, 141.3, 144.1, 144.6; MS (ESI): m/z = 361.1 [M+H] +. 1-(2,2,2-Triphenyl-ethyl)-1H-benzoimidazole (31). Synthesized from 28a (1.13 g, 2.63 mmol), benzimidazole (622 mg, 5.26 mmol) and K2CO3 (1.82 g, 13.2 mmol) in DMF according to Method A. White solid. Yield: 314 mg, 0.84 mmol, 32 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 4.24 (s, 2H), 6.52 (d, J = 7.6 Hz, 2H), 6.56 (d, J = 8.5 Hz, 1H), 6.94 – 7.01 (m, 3H), 7.11 (t, J = 7.3 Hz, 7.19 (dt, J = 0.9 Hz, 7.6 Hz, 1H), 7.28 – 7.32 (m, 10H), 7.79 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H);

13

C NMR (CDCl3, 125 MHz): δC (ppm) = 44.88, 71.19,

114.5, 120.5, 121.9, 122.4, 127.1, 127.8, 127.9, 128.0, 128.4, 130.5, 134.0, 135.3, 141.4, 143.8, 144.6; MS (ESI): m/z = 375.0 [M+H] +. 1-(3,3,3-Triphenyl-propyl)-1H-benzoimidazole (32). Synthesized from 29a (800 mg, 1.81 mmol), benzimidazole (428 mg, 3.62 mmol) and K2CO3 (1.25 g, 9.05 mmol) in DMF according to Method A. White solid. Yield: 240 mg, 0.62 mmol, 34 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 3.11 – 3.14 (m, 2H), 3.97 – 4.00 (m, 2H), 7.11 – 7.14 (m, 1H), 7.24 – 7.29 (m, 5H), 7.33 – 7.38 (m, 12H), 7.74 (s, 1H), 7.79 – 7.82 (m, 1H);

13

C NMR (CDCl3, 125

MHz): δC (ppm) = 40.60, 42.17, 55.64, 109.4, 120.4, 122.0, 122.8, 126.5, 128.3, 128.8, 133.5, 142.6, 143.8, 145.9; MS (ESI): m/z = 389.13 [M+H] +. 2-Bromo-5-(bromomethyl)pyridine (33b). 2-Bromo-5-methylpyridine (3.00 g, 17.40 mmol) was dissolved in 40 mL of dry carbon tetrachloride. To this solution was added Nbromsuccinimide (NBS) (3.41 g, 19.20 mmol) and benzoyl peroxide (0.23 g, 0.80 mmol) and the mixture was refluxed over night. After cooling, the succinimide was removed by filtration

16

and the filtrate was concentrated under vacuum. The crude product was further purified by flash column chromatography on silica gel using a mixture of petroleum ether / EtOAc (95:5) as eluent; yield: 2.56 g (59 %); lachrymatory yellow needles; 1H NMR (CDCl3, 500 MHz): δH (ppm) = 4.14 (s, 2H), 7.47 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 8.38 (s, 1H); MS (ESI): m/z = 252.4 [M+H] +. 5-((1H-Imidazol-1-yl)methyl)-2-bromopyridine (33a). Synthesized using 33b (1.32 g, 5.26 mmol), imidazole (0.75 g, 11.00 mmol), K2CO3 (1.13 g, 8.16 mmol) and 18-crown-6 according to Method A. Yellow solid. Yield: 0.75 g, 60 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.12 (s, 2H), 6.88 (t, J = 1.2 Hz, 1H), 7.13 (s, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 8.28 (d, J = 2.5 Hz, 1H); MS (ESI): m/z = 239.1 [M+H] +. 5-((1H-Imidazol-1-yl)methyl)-2-phenylpyridine (33). Synthesized using compound 33a (0.20 g, 0.84 mmol) and phenylboronic acid (0.20 g, 1.68 mmol) according to Method B. Yellow solid. Yield: 0.10 g, 57 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.19 (s, 2H), 6.94 (t, J =1.3 Hz, 1H), 7.13 (s, 1H), 7.48-7.50 (m, 4H), 7.60 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.97-7.99 (m, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 48.1, 119.0, 120.6, 126.9, 128.8, 130.0, 130.4, 135.7, 137.3, 138.6, 148.6, 157.7; MS (ESI): m/z = 236.0 [M+H] +.

(5-Phenyl-furan-2-yl)-methanol (34a). Synthesized using 5-phenyl-furan-2-carboxylic acid (376 mg, 2.00 mmol) and LiAlH4 (114 mg, 3.00 mmol) according to Method C. Yield: 157 mg, 46 %; The compound was directly used in the next step without further purification. 1-(5-Phenyl-furan-2-ylmethyl)-1H-imidazole (34). Synthesized using compound 34a (137 mg, 0.80 mmol) and CDI (258 mg, 1.59 mmol) according to Method F. Yellow solid. Yield: 87 mg, 48 %; 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.14 (s, 2H), 6.38 (d, J = 3.5 Hz, 1H), 6.59 (d, J = 3.5 Hz, 1H), 7.01 (brs, 1H), 7.08 (brs, 1H), 7.27 – 7.29 (m, 1H), 7.38 (t,

17

J = 7.8 Hz, 2H), 7.59 (brs, 1H), 7.61 – 7.63 (m, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 43.8, 105.7, 111.0, 119.0, 123.8, 127.8, 128.7, 129.7, 130.2, 137.1, 148.3, 154.7; MS (ESI): m/z = 224.9 [M+H] +. 5-Phenyl-thiophene-2-carbaldehyde

(35b).

Synthesized

using

5-bromo-thiophene-2-

carbaldehyde (955 mg, 5.00 mmol) and phenylboronic acid (1.22 g, 10.0 mmol) according to Method B; yield: 931 mg (99 %); 1H NMR (CDCl3, 500 MHz): δH (ppm) = 7.32-7.38 (m, 4H), 7.59-7.61 (m, 2H), 7.67 (d, J = 3.8 Hz, 1H), 9.82 (s, 1H);

13

C NMR (CDCl3, 125 MHz): δC

(ppm) = 123.1, 125.4, 128.2, 128.4, 132.1, 136.3, 141.5, 153.3, 181.8; MS (ESI): m/z = 189.0 [M+H] +. (5-Phenyl-thiophen-2-yl)-methanol

(35a).

Synthesized

using

5-phenyl-thiophene-2-

carbaldehyde (376 mg, 2.00 mmol) and NaBH4 (136 mg, 3.60 mmol) according to Method C. Yield: 349 mg, 92 %; 1H NMR (CDCl3, 500 MHz): δH (ppm) = 1.85 (t, J = 6.0 Hz, 1H), 4.82 (d, J = 6.0 Hz, 2H), 6.98 (d, J = 3.7 Hz, 1H), 7.17 (d, J = 3.7 Hz, 1H), 7.28 (tt, J = 1.4 Hz, J = 7.5 Hz, 1H), 7.38 (dd, J = 7.5 Hz, J = 8.4 Hz, 2H), 7.59 (dd, J = 1.4 Hz, J = 8.4 Hz, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 60.3 (CH2), 122.8 (CH), 125.8 (CH), 126.5 (CH), 127.5, 128.9, 134.3, 143.3, 144.7. MS (ESI): m/z = 173.3 [M-H2O] +. 1-(5-Phenyl-thiophen-2-ylmethyl)-1H-imidazole (35). Synthesized using compound 35a (190 mg, 1.00 mmol) and CDI (324 mg, 2.00 mmol) according to Method F. Yield: 127 g, 53 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.27 (s, 2H), 6.94 (d, J = 3.7 Hz, 1H), 6.99 (brs, 1H), 7.09 (brs, 1H), 7.15 (d, J = 3.7 Hz, 1H), 7.27 – 7.31 (m, 1H), 7.37 (t, J = 7.8 Hz, 2H), 7.53 – 7.55 (m, 2H), 7.59 (brs, 1H);

13

C NMR (CDCl3, 125 MHz): δC (ppm) = 45.77,

118.9, 122.9, 125.8, 127.8, 127.9, 129.0, 129.9, 133.8, 137.0, 139.0, 142.2; MS (ESI): m/z = 241.1 [M+H] +. 4-Phenylthiophene-2-carbaldehyde (36b). Synthesized using phenylboronic acid (0.49 g, 2.00 mmol) and 4-bromothiophen-2-carbaldehyde (0.38 g, 2.00 mmol) according to Method B. White solid. Yield: 0.35 g, 93 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 7.36 (mc, 1H), 18

7.44 (dd, J = 7.3, 7.9 Hz, 2H), 7.59 (dd, J = 1.3 Hz, 8.5 Hz, 2H), 7.85 (dd, J = 1.3 Hz, 1.6 Hz, 1H), 8.03 (d, J = 1.6 Hz, 1H), 9.97 (d, J = 1.3 Hz, 1H);

13

C NMR (CDCl3, 125 MHz): δC

(ppm) = 115.3, 126.3, 128.0, 129.1, 129.6, 134.4, 143.7, 144.4, 183.0; MS (ESI): m/z = 189.3 [M+H] +. 4-Phenyl-2-thiophenemethanol (36a). Synthesized according to Method C using 36b (0.31 g, 1.60 mmol) and NaBH4 (0.11 g, 2.90 mmol). White solid. Yield: 0.27 g, 88 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 1.89 (brs, 1H), 4.86 (s, 2H), 7.28-7.32 (m, 2H), 7.39 (d, J = 1.6 Hz, 1H), 7.40 (dd, J = 7.3, 8.0 Hz, 2H), 7.57 (dd, J = 1.6, 8.0 Hz, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm) = 60.3, 120.3, 124.7, 126.3, 127.2, 128.8, 135.8, 142.1, 144.8; MS (ESI): m/z = 173.2 [M-H2O] +. 1-((4-Phenylthiophen-2-yl)methyl)-1H-imidazole (36). Synthesized using 36a (0.19 g, 1.00 mmol) and CDI (0.24 g, 1.50 mmol) according to Method F. Light brown solid. Yield: 0.09 g, 38 %. 1H NMR (CDCl3, 500 MHz): δH (ppm) = 5.29 (s, 2H), 7.00 (t, J = 1.3 Hz, 1H), 7.10 (bs, 1H), 7.24-7.25 (m, 1H), 7.30 (tt, J = 1.3, 7.5 Hz, 1H), 7.38 (d, J = 1.6 Hz, 1H), 7.39 (dd, J = 7.5, 7.8 Hz, 2H), 7.53 (dd, J = 1.3, 7.8 Hz, 2H), 7.60 (s, 1H);

13

C NMR (CDCl3,

125 MHz): δC (ppm) = 45.7, 118.9, 120.8, 126.0, 126.3, 127.5, 128.9, 130.0, 135.2, 137.0, 139.2, 142.4; MS (ESI): m/z = 241.1 [M+H] +.

19