Journal of Medicinal Chemistry 138.19, 134.28, 133.48, 132.33, 131.81 (d, 4JCF = 3), 129.95 (d, 3JCF = 8), 126.67, 125.55, 117.89, 115.81, 115.47 (d, 2JCF = 21), 69.52, 43.90 (C B(OH)2 not visible). MS: m/z [MþH]þ calc. 464.11, obs. 464.19. For experimental details of compounds 17 20, 26, and E-28 see Supporting Information. (4-((4-((3-(4-Fluorobenzyl)-2,4-dioxothiazolidin-5-yl)methyl) phenoxy)methyl) phenyl)boronic Acid (21). A mixture of com- pound 1 (50.1 mg, 0.108 mmol) and 10 wt % Pd/C (24.0 mg) in degassed methanol (3 mL) was stirred under a hydrogen atmosphere for 2 h. Extra 10 wt % Pd/C was added (12.0 mg) and the reaction was allowed to continue for one night. The mixture was filtrated and concentrated to dryness. Preparative HPLC afforded the title com- pound. Yield: 18.3 mg, 77%. 1H NMR: δ = 8.03 (s, 2H), 7.80 (d, J = 8.1, 2H), 7.39 (d, J = 8.1, 2H), 7.28 6.99 (m, 6H), 6.88 (d, J = 8.7, 2H), 5.06 (s, 2H), 5.00 (dd, J = 4.4, 8.0, 1H), 4.60 (dd, J = 15.0, 21.5, 2H), 3.14 (dd, J = 8.0, 14.2, 1H). 13C NMR: δ = 173.71, 171.00, 161.50 (d, 1JCF = 244), 157.44, 138.74, 134.16, 131.58 (d, 4JCF = 3), 130.56, 129.66 (d, 3JCF = 8), 127.98, 126.52, 115.21 (d, 2JCF = 21), 114.57, 69.12, 50.94, 43.56, 35.79 (C B(OH)2 not visible). MS: m/z [MþH]þ calc. 466.13, obs. 466.25, [M-H2OþH]þ calc. 448.12, obs. 448.23. (4-((4-((3-(4-Fluorobenzyl)-4-hydroxy-2-oxothiazolidin-5- yl)methyl)phenoxy) methyl)phenyl)boronic Acid (22). To a solution of compound 1 (50.0 mg, 0.108 mmol) in dimethyl sulfoxide (0.5 mL), sodium borohydride (16.3 mg, 0.430 mmol) was slowly added. After 9 h of stirring, the reaction mixture was diluted with ethyl acetate (4 mL) and was washed with water (2 2 mL). The organic layer was dried over calcium chloride and concentrated in vacuo, resulting in the title compound. Yield: 30.2 mg, 60%. 1H NMR: δ = 8.06 (s, 2H), 7.80 (d, J = 8.1, 2H), 7.39 (d, J = 8.0, 2H), 7.36 7.11 (m, 5H), 6.94 (d, J = 8.7, 2H), 6.87 (d, J = 8.7, 2H), 6.71 (d, J = 6.2, 1H), 5.06 (s, 2H), 4.72 (dd, J = 7.7, 15.1, 1H), 4.10 (d, J = 15.1, 1H), 3.67 (t, J = 7.9, 1H), 3.35 (s, 1H), 2.81 (dd, J = 7.3, 13.9, 1H), 2.70 (dd, J = 8.4, 13.9, 1H). 13C NMR: δ = 169.70, 161.55 (d, 1JCF = 244), 157.13, 138.85, 134.15, 133.14 (d, 4JCF = 3.0), 130.01, 130.00 (d, 3JCF = 8), 129.73, 126.54, 115.38 (d, 2JCF = 21), 114.64, 84.02, 69.11, 51.42, 44.02, 39.65. (C B(OH)2 not visible). MS: m/z [MþH]þ calc. 468.15, obs. 468.23. (4-((4-((3-(4-Fluorobenzyl)-2-oxo-2,3-dihydrothiazol-5-yl) methyl)phenoxy) methyl)phenyl)boronic Acid (23). To a solution of compound 1 (45.7 mg, 0.0989 mmol) in dimethyl sulfoxide (0.75 mL), sodium borohydride (29.1 mg, 0.769 mmol) was slowly added. After 7 h of stirring the reaction mixture, concentrated sulfuric acid (2 50 μL) was added over a 15 min interval. The reaction mixture was stirred for an additional 5 h. Ethyl acetate (25 mL) was added and the mixture was washed with water (4 10 mL). The organic layer was dried over calcium chloride and concentrated in vacuo, affording pure compound 23. Yield: 31.8 mg, 72%. 1H NMR: δ = 8.05 (s, 2H), 7.79 (d, J = 8.1, 2H), 7.38 (d, J = 8.1, 2H), 7.36 7.16 (m, 4H), 7.13 (d, J = 8.7, 2H), 6.95 (d, J = 8.7, 2H), 6.87 (s, 1H), 5.07 (s, 2H), 4.80 (s, 2H), 3.73 (s, 2H). 13C NMR: δ = 170.43, 161.61 (d, 1JCF = 244), 157.13, 138.85, 134.17, 133.10 (d, 4JCF = 3), 130.63, 130.63, 129.76 (d, 3JCF = 8), 129.42, 126.48, 121.56, 117.78, 115.50 (d, 2JCF = 21), 114.86, 69.16, 46.78, 32.91 (C B(OH)2 not visible). MS: m/z [MþH]þ calc. 450.13, obs. 450.22. 3-(4-Fluorobenzyl)imidazolidine-2,4-dione (25). To a cooled solution (273 K) of hydantoin (8.01 g, 80.1 mmol) in dimethylformamide (140 mL) sodium hydride (60% in oil, 1.80 g, 45.0 mmol) was added. A solution of 1-(bromomethyl)-4-fluorobenzene (5.0 mL, 41 mmol) in dimethylformamide (5 mL) was added to the reaction mixture. The mixture was allowed to warm up to room temperature and was stirred for 6 h. Then, the mixture was poured into water (200 mL) and hexane (200 mL) was added. After a night at 277 K, the precipitate was filtered and dried to give a white solid. Yield: 4.7 g, 56%. 1H NMR: δ = 8.14 (s, 1H), 7.45 7.21 (m, 1H), 7.26 7.09 (m, 1H), 4.51 (s, 2H), 3.97 (s, 2H). 13C NMR: δ = 171.91, 161.45 (d, 1JCF = 244), 157.29, 133.04 (d, 4JCF = ARTICLE 3), 129.66 (d, 3JCF = 8), 115.21 (d, 2JCF = 21), 46.00, 40.29. MS: m/z [MþH]þ calc. 209.07, obs. 208.93. 3-(4-Fluorobenzyl)-1-methylimidazolidine-2,4-dione (27). To a cooled solution (273 K) of 3-(4-fluorobenzyl)imidazolidine-2,4-dione (98.1 mg, 0.471 mmol) in dimethylformamide (0.5 mL), sodium hydride (60% in oil, 21.1 mg, 0.530 mmol) was added. Subsequently, iodomethane (33 μL, 0.53 mmol) was added to the reaction mixture. The mixture was allowed to warm up to room temperature and was stirred for 3 h. Then, the mixture was poured into ice water (2.5 mL) and hexane (2.5 mL) was added. After a night at 277 K, the precipitate was filtered and dried to give a white solid. Yield: 75 mg, 72%. 1H NMR: δ = 7.34 7.12 (m, 4H), 4.52 (s, 2H), 4.01 (s, 2H), 2.86 (s, 3H). 13C NMR: δ = 170.20, 161.46 (d, 1JCF = 244), 156.24, 132.92 (d, 4JCF = 3), 129.68 (d, 3JCF = 8), 115.21 (d, 2JCF = 21), 51.36, 40.74, 29.21. MS: m/z [MþH]þ calc. 223.09, obs. 223.06. (Z)-(4-((4-((1-(4-Fluorobenzyl)-3-methyl-2,5-dioxoimidazoli- din-4-ylidene)methyl) phenoxy)methyl)phenyl)boronic Acid (Z-28). To a cooled solution (273 K) of hydantoine 26 (10.1 mg, 0.0224 mmol) and sodium hydride (60% in oil, 1.46 mg, 0.0365 mmol) in DMF (0.15 mL), iodomethane (2.25 μL, 0.0361 mmol) was added. The mixture was allowed to warm up to room temperature and was stirred for 4 h. Final product was isolated by using preparative HPLC. Z-configuration confirmed by the chemical shift of the vinyl and methyl proton reported in literature.23 Yield: 6.97 mg, 68%. 1H NMR: δ = 8.11 (s, 1H), 7.80 (d, J = 8.1, 2H), 7.50 7.30 (m, 6H), 7.26 7.10 (m, 2H), 7.05 (d, J = 8.8, 2H), 6.76 (s, 1H), 5.14 (s, 2H), 4.67 (s, 2H), 2.92 (s, 3H). 13C NMR: δ = 163.01, 159.92, 156.78 (d, 1JCF = 249), 138.52, 134.19, 132.55 (d, 4JCF = 3), 131.28, 129.75 (d, 3JCF = 8), 128.50, 126.58, 124.66, 115.31 (d, 2JCF = 21), 114.55, 111.56, 69.30, 41.12, 30.35 (C B(OH)2 not visible). MS: m/z [MþH]þ calc. 461.17, obs. 461.12. (E)-(4-((4-((2,5-Dioxopyrrolidin-3-ylidene)methyl)phenoxy) methyl)phenyl)boronic Acid (31). To a heated (343 K) solution of compound 30 (159 mg, 0.442 mmol)16 in methanol (5 mL) aldehyde 12 (106 mg, 0.414 mmol) was added. After 1 h of heating, the reaction mixture was cooled using an ice bath resulting in precipitation of the title compound. The precipitate was filtered and washed with ice-cold methanol resulting in compound 31. Yield: 88 mg, 63%. 1H NMR: δ = 11.34 (s, 1H), 8.04 (s, 2H), 7.80 (d, J = 8.0, 2H), 7.57 (d, J = 8.9, 2H), 7.41 (d, J = 8.0, 2H), 7.33 (t, 4J = 2.1, 1H), 7.10 (d, J = 8.8, 2H), 5.19 (s, 2H), 3.60 (d, 4J = 2.2, 2H). 13C NMR: δ = 175.80, 172.09, 159.47, 138.42, 134.22, 132.00, 131.31, 126.96, 126.54, 124.16, 115.31, 69.31, 34.71 (C B(OH)2 not visible). MS: m/z [MþH]þ calc. 338.12, obs. 338.11. (E)-(4-((4-((1-(4-Fluorobenzyl)-2,5-dioxopyrrolidin-3-ylidene) methyl)phenoxy) methyl)phenyl)boronic Acid (32). To a solution of compound 31 (30 mg, 0.0890 mmol) in dimethylformamide (0.3 mL) sodium hydride (60% in oil, 3.65 mg, 0.0913 mmol) was added. After addition of 4-fluorobenzyl bromide (24 μL, 0.19 mmol), the reaction mixture was stirred for 4 h. In addition, potassium carbonate (2.04 mg, 0.0148 mmol) was added and the reaction mixture was stirred overnight. Then, the mixture was poured into ice water (0.9 mL) and hexane (0.3 mL) was added. After a night at 277 K, the precipitate was filtered, dried, and purified using preparative HPLC to give a white solid. E-Configuration confirmed by the chemical shift of the vinyl proton reported in literature.16 Yield: 13 mg, 32%. 1H NMR: δ = 8.04 (s, 2H), 7.80 (d, J = 8.1, 2H), 7.61 (d, J = 8.9, 2H), 7.45 (t, 4J = 2.1, 1H), 7.41 (d, J = 8.0, 2H), 7.38 7.29 (m, 2H), 7.23 7.04 (m, 4H), 5.19 (s, 2H), 4.66 (s, 2H), 3.74 (d, 4J = 2.1, 2H). 13C NMR: δ = 174.19, 170.59, 161.44 (d, 1JCF = 244), 159.65, 138.39, 134.22, 132.59 (d, 4JCF = 3), 132.31, 132.17, 129.73 (d, 3JCF = 8), 126.85, 126.54, 122.27, 115.36, 115.22 (d, 2JCF = 21), 69.33, 40.71, 33.74 (C B(OH)2 not visible). MS: m/z [MþH]þ calc. 446.16, obs. 446.12. (S)-2-(4-Fluorobenzyl)-7-hydroxy-10,10a-dihydroimidazo- [1,5-b]isoquinoline-1,3(2H,5H)-dione (S-34). Compound S-33 (100 mg, 0.518 mmol) was dissolved in a mixture of dioxane and water 4624 dx.doi.org/10.1021/jm200310q |J. Med. Chem. 2011, 54, 4619–4626