Solid Phase Synthesis of Triazadibenzoazulenone [1]

Abstract

An efficient solid phase strategy for the preparation of a novel heterocyclic ring system triazadibenzoazulenone has been ­described. The method has been successfully used for the synthesis of a library of 48 compounds from structurally diverse amino acids, o-fluoronitrobenzenes and o-nitrobenzaldehydes in high yields and purities using an automated synthesizer.

combinatorial chemistry - solid-phase synthesis - heterocyclic - cyclization - azulenone

References

1

CDRI Communication No. 6576.

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5

General Experimental Procedure for I: The Fmoc groups of Rink Amide AM resin were removed by treating with 25% piperidine in DMF (1 mL) twice for 5 min and 25 min. The resin was filtered and washed with DMF (9 × 5 mL). The resin so obtained was coupled with Fmoc protected amino acids (10 fold) by using HOBt (10 fold), DIC (10 fold) and DMF (1 mL) as solvent for 16 h at r.t. The resin was filtered and washed successively with DMF (3 × 2 mL), MeOH (3 × 2 mL), CH₂Cl₂ (3 × 2 mL) and Et₂O (3 × 2 mL) and finally dried in vacuo. Completion of the reaction was confirmed by a negative Kaiser test. The Fmoc groups of the resulting resin were removed by treating with 25% piperidine in DMF (1 mL) twice for 5 min and 25 min. The resin was filtered and washed with DMF (9 × 5 mL). The resin so obtained was treated with 1-fluoro-2-nitrobenzenes (10 fold) and DIPEA (10 fold) in DMSO at 60 °C for 16 h. The resin was filtered and washed successively with DMF (3 × 2 mL), MeOH (3 × 2 mL), CH₂Cl₂ (3 × 2 mL) and Et₂O (3 × 2 mL) and finally dried in vacuo. The nitro group of resin 2 was reduced to amine with 2 M SnCl₂·2H₂O in DMF (1 mL) for 5 h at r.t. Thereupon the resin was washed successively with DMF (3 × 2 mL), MeOH (3 × 2 mL), CH₂Cl₂ (3 × 2 mL) and Et₂O (3 × 2 mL) and finally dried in vacuo to give 3. Resin 3 was treated with o-nitrobenzaldehydes (10 fold) in DMF at 60 °C for 16 h. The resin was filtered and washed successively with DMF (3 × 2 mL), MeOH (3 × 2 mL), CH₂Cl₂ (3 × 2 mL) and Et₂O (3 × 2 mL) and finally dried in vacuo to leave benzimidazoles 4. The nitro group of resin 4 was reduced to amine with 2 M SnCl₂·2H₂O in DMF (1 mL) for 5 h at r.t. and then washed successively with DMF (3 × 2 mL), MeOH (3 × 2 mL), CH₂Cl₂ (3 × 2 mL) and Et₂O (3 × 2 mL) and finally dried in vacuo to give 5. Finally resin 5 was subjected to cyclization and cleavage with a mixture of 10% HOAc in CH₂Cl₂ (1 mL) for 16 h at r.t. The resulting mixture was filtered and evaporated to dryness in vacuo. The residue was freeze dried by dissolving in t-BuOH-H₂O (4:1) to give the desired compounds I as acetate salts in >80% yields and >92% purities.

6

The quaternization of the nitrogen at N-12 in compound Ig was established by 1D NOE difference studies. Irradiation of -NH at δ = 10.69 ppm showed 15% enhancement of ortho doublet -CH at δ = 7.29 ppm. Further irradiation of the doublet at δ = 7.29 ppm gave 14% enhancement of the -NH at δ = 10.69 ppm. The above results established the close proximity of the -NH at δ = 10.69 ppm with the ortho doublet, which clearly suggests the quaternization of the nitrogen at N-12.

7

10-Fluoro-6-oxo-6,7-dihydro-5 H -5,7a-diaza-12-azonia-dibenzo[ a , e ]azulene Acetate (Ig): ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.50 (s, 3 H, CH₃), 4.97 (s, 2 H, CH₂), 7.23 (td, 1 H, J = 9.3 Hz, J = 2.4 Hz, ArH), 7.29 (d, 1 H, J = 8.1 Hz, ArH), 7.37 (t, 1 H, J = 7.5 Hz, ArH), 7.55 (dd, 1 H, J = 10.2 Hz, J = 1.8 Hz, ArH), 7.61 (d, 1 H, J = 7.2 Hz, ArH), 7.89 (dd, 1 H, J = 6.0 Hz, J = 4.6 Hz, ArH), 8.08 (d, 1 H, J = 7.8 Hz, ArH), 10.66 (s, 1 H, NH⁺). Anal. Calcd for C₁₅H₁₀FN₃O·CH₃COOH: C, 62.38; H, 4.31; N, 12.84%. Found: C, 62.53; H, 4.27; N, 12.88%.
6-Oxo-6,7-dihydro-5 H -5,7a-diaza-12-azonia-dibenzo[ a , e ]azulene Acetate (Ik): ¹H NMR (300 MHz, DMSO-d ₆): δ = 2.50 (s, 3 H, CH₃), 4.99 (s, 2 H, CH₂), 7.41 (overlapped, 3 H, 3 × ArH), 7.54 (d, 1 H, J = 8.4 Hz, ArH), 7.60 (t, 1 H, J = 7.8 Hz, ArH), 7.71 (t, 1 H, J = 6.4 Hz, ArH), 7.82 (d, 1 H, J = 6.9 Hz, ArH), 8.08 (d, 1 H, J = 7.8 Hz, ArH), 10.69 (s, 1 H, NH⁺). Anal. Calcd for C₁₅H₁₁N₃O·CH₃COOH: C, 66.01; H, 4.89; N, 13.58%. Found: C, 66.19; H, 4.85; N, 13.53%.