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DOI: 10.1055/s-2004-829077
A Solid-Phase Approach to Fluorobenzimidazoles and Fluoro-2-hydroxyquinoxalines Using ’One-Bead-Two-Compound’ Method
Publication History
Publication Date:
29 June 2004 (online)
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Abstract
A solid-phase approach to fluorobenzimidazoles 6a and fluoro-2-hydroxyquinoxalines 6b has been achieved by a new strategy of ‘one-bead-two-compound’. The precursor, 6-nitro-2,3,4,5-tetrafluorobenzoic acid, was tagged to Rink amide MBHA resin via an α-amino acid linker. The first nucleophilic substitution generated two regioisomers in which the second active fluorine atom underwent a subsequent nucleophilic substitution with a primary amine. The reduction of the aryl nitro groups with SnCl2〈2H2O/NMM and the formation of a five-membered ring with aldehydes afforded 4b and 5a. Fluorobenzimidazoles 6a were directly furnished by cleavage using TFA, therewith the stable six-membered ring 6b was produced by concomitant intramolecular cyclization and thermal dehydrogenation. In addition to introduction of fluorine into the heterocycles, two scaffolds could be simultaneously synthesized with this method.
Key words
solid-phase synthesis - fluorobenzimidazoles - fluoro-2-hydroxyquinoxalines - regioselectivity - ‘one-bead-two-compound’
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General Procedure for the Synthesis of 6a and 6b: Amino acid-bound Rink amide MBHA resin 1 (200 mg) was mixed with NTFBA (5.0 equiv) in DMF (5 mL). After shaking for 3 h at r.t. the resin was filtered and washed with DMF (3 ¥ 5 mL), CH2Cl2 (3 ¥ 5 mL) and MeOH (3 ¥ 5 mL). The resin was treated with a large excess of primary aliphatic amine (10.0 equiv) in DMF (5 mL) overnight at r.t. followed by washing with DMF (3 ¥ 5 mL), CH2Cl2 (3 ¥ 5 mL) and MeOH (3 ¥ 5 mL). The diamines 3a and 3b were reduced with 2 M SnCl2〈2H2O/2 M NMM in DMF (5 mL) overnight at r.t. under an argon atmosphere. After quick washing with DMF (6 ¥ 5 mL), CH2Cl2 (3 ¥ 5 mL) and MeOH (3 ¥ 5 mL), the triamines 4a and 4b were treated with 10.0 equiv aldehyde in HOAc-DMF (4:96, 5 mL). After shaking for 72 h at r.t. the resin was washed with DMF (4 ¥ 5 mL), CH2Cl2 (4 ¥ 5 mL) and MeOH (4 ¥ 5 mL). The washed resin was cleaved with TFA-H2O (95:5, 5 mL) for 50 min at r.t. and then the remaining resin was rinsed with CH2Cl2 (3 ¥ 3 mL) and MeOH (3 ¥ 3 mL). The combined solvents were evaporated under vacuum and the residue was refluxed in MeOH (8 mL) for 10 h to give the final products 6a and 6b. The target compounds were easily separated with reverse-phase column chromatography with a gradient elution from MeCN-H2O (9:1) to MeCN-H2O (1:9) in 10% alternation.
11Selected spectroscopic data for 6a-I: yellow oil. 1H NMR (500 MHz, CDCl3): δ = 1.11 [d, J = 7.0 Hz, 6 H, CH(CH
3)2], 2.39 [m, 1 H, CH(CH3)2], 3.08 (t, J = 6.5 Hz, 2 H, PhCH
2CH2N), 3.65 (t, J = 6.5 Hz, 2 H, PhCH2CH
2N), 3.79 (d, J = 4.0 Hz, 1 H, NHCHCHCONH2), 3.89 [s, 6 H,
Ar-(OCH
3)2], 3.93 (s, 3 H, Ar-OCH
3), 4.78 (br s, 1 H, NH), 5.75 (s, 1 H, CONHH), 6.41 (s, 1 H, CONHH), 6.67 (s, 2 H, Ar-H
2), 6.71 (d, J = 7.5 Hz, 2 H, o-Ar-H
2
), 7.15 (dd, J = 7.5 Hz, J = 7.0 Hz, 2 H, m-Ar-H
2
), 7.20 (d, J = 7.0 Hz, 1 H,
p-Ar-H), 7.69 (d, J
H-F = 10.0 Hz, 1 H, Ar-H). ESI-MS: m/z = 539.2 [M + H+]. HRMS-FAB: m/z [M + H]+ calcd for C28H33F2N4O4, 539.2470; found, 539.2823. For 6b-I: white solid; mp 179.3 °C. 1H NMR (500 MHz, CDCl3): δ = 1.35 [d, J = 7.0 Hz, 6 H, CH(CH
3)2], 2.90 (t, J = 6.5 Hz, 2 H, PhCH
2CH2), 3.61 [sep, J = 7.0 Hz, 1 H, CH(CH3)2], 3.64 (t, J = 6.5 Hz, 1 H, PhCH2CH
2N), 6.81 (d, J
F-H = 11.0 Hz, 1 H, Ar-H), 7.20 (d, J = 7.5 Hz, 2 H, o-Ar-H
2
), 7.23 (d, J = 7.0 Hz, 1 H, p-Ar-H), 7.32 (dd, J = 7.5 Hz, J = 7.0 Hz, 2 H,
m-Ar-H
2
), NH and OH were not observed. ESI-MS: m/z = 344.1 [M + H+]. HRMS-FAB: m/z [M + H]+ calcd for C19H20F2N3O, 344.1574; found, 344.1809.