Novel Approach towards the Synthesis of 3,3a,4,5-Tetrahydroquinolino[4,3-c]isoxazole Derivatives: Application to the Preparation of Previously Unattainable 3a,4-Dihydroazabenzopyrano[4,3-c]isoxazole Scaffolds

Abstract

A novel synthetic approach towards the preparation of 3-substituted-7,8-dimethoxy-3,3a,4,5-tetrahydroquinolino[4,3-c]isoxazole derivatives is reported. Further application of this methodology to the preparation of previously unattainable 3a,4-dihydroazabenzopyrano[4,3-c]isoxazole derivatives is also described.

isoxazolines - fused-ring systems - ring closure - heterocycles - antidepressants

References

1 Andrés JI. Alcázar J. Alonso JM. Alvarez RM. Cid JM. De Lucas AI. Fernández J. Martínez S. Nieto C. Pastor J. Bakker MH. Biesmans I. Heylen LI. Megens AA. Bioorg. Med. Chem. Lett.  2003,  13:  2719 

2 Pastor J. Alcázar J. Alvarez RM. Andrés JI. Cid JM. De Lucas AI. Díaz A. Fernández J. Lafuente C. Martínez S. Bakker MH. Biesmans I. Heylen LI. Megens AA. Bioorg. Med. Chem. Lett.  2004,  14:  2917 

3a Andrés JI. Alcázar J. Alonso JM. Alvarez RM. Bakker MH. Biesmans I. Cid JM. De Lucas AI. Fernández J. Font LM. Hens KA. Iturrino L. Lenaerts I. Martínez S. Megens AA. Pastor J. Vermote CM. Steckler T. J. Med. Chem.  2005,  48:  2054 

3b Andres-Gil JI, Alcazar-Vaca MJ, Bartolome-Nebreda JM, Fernandez-Gadea FJ, Bakker MHM, and Megens AAHP. inventors; PCT Int. Appl. WO  2004018483.  ; Chem. Abstr. 2004, 140, 217631

3c Andres-Gil JI, Fernandez-Gadea FJ, Alcazar-Vaca MJ, Cid-Nunez JM, Pastor-Fernandez J, Megens AAHP, Heylen GICM, Langlois XJM, Bakker MHM, and Steckler THW. inventors; PCT Int. Appl. WO  2002066484.  ; Chem. Abstr. 2002, 137, 201298

4 Baraldi PG. Bigoni A. Cacciari B. Caldari C. Manfredini S. Spalluto G. Synthesis  1994,  1158 

5

The absence of water during the reduction step is crucial in order to keep the stereochemistry of both stereocenters, otherwise a mixture of both diastereoisomers is obtained.

6

Synthesis of Compound 6 from 5.
A solution of compound 5 (5.3 mmol, 2.5 g) in THF-H₂O (7.5/1, 85 mL) was hydrogenated at 40 psi of hydrogen in the presence of 10% Pd/C (0.25 g) at r.t. for 24 h. Then the catalyst was removed by filtration over Celite^® and the filtrate was concentrated and extracted with CH₂Cl₂. The organic layer was separated, dried (Na₂SO₄), filtered and evaporated. The residue obtained (2.36 g, 5.3 mmol, 100%) was dissolved in THF (50 mL) and Et₃N (13.25 mmol, 1.85 mL) was added. The resulting solution was stirred at reflux for 24 h and then sat. NaHCO₃ was added. The mixture was extracted with CH₂Cl₂ and the organic layer was separated, dried (Na₂SO₄), filtered and evaporated. The residue was purified by short open-column chromatography on silica gel (CH₂Cl₂-EtOAc, 4:1 and EtOAc) yielding compound 6 as a colorless syrup (4 mmol, 1.36 g, 75%).
Representative analytical data for compound 6: foam. ¹H NMR (400 MHz, DMSO-d ₆, 25 °C): δ = 6.90 (s, 1 H, H-9), 6.30 (s, 1 H, H-6), 6.12 (s, 1 H, NH), 4.62 (m, 1 H, CH₂OMs), 4.50 (m, 2 H, H-3 and CH₂OMs), 3.72 (s, 3 H, CH₃O), 3.68 (s, 3 H, CH₃O), 3.45-3.65 (m, 2 H, H-4), 3.23 (s, 3 H, CH₃SO₂O), 3.15 (m, 1 H, H-3a). ESI-HRMS: m/z calcd for C₁₄H₁₈N₂O₆S [MH]⁺: 343.0958; found: 343.0963.

7 Ronald RC. Winkle MR. Tetrahedron  1983,  39:  2031 

8

Several attempts to convert the alkyl hydroxy groups into leaving groups suitable for further intramolecular O-alkylation failed.

9

Synthesis of Compound 11 from 10.
To a solution of 10 (2.72 mmol, 0.61 g) in THF (10 mL), in a sealed tube under N₂, Et₃N (2.72 mmol, 0.38 mL), polymer supported PPh₃ (5.44 mmol, 1.81 g) and diethyl azodicarboxylate (3.41 mmol, 0.67 mL) were added. The reaction mixture was stirred at reflux for 16 h and then filtered through Celite^®. The Celite^® pad was washed with MeOH and the combined filtrates were evaporated. The residue was re-dissolved in CH₂Cl₂ and washed with brine, dried (Na₂SO₄), filtered and evaporated. The residue was purified by flash-column chromatography on silica gel (EtOAc) yielding compound 11 as a white foam (2.66 mmol, 0.55 g, 98%).
Representative analytical data for compound 11: syrup. ¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 8.41 (s, 1 H, H-6), 8.27 (d, J = 5.1 Hz, 1 H, H-8), 7.59 (d, J = 5.0 Hz, 1 H, H-9), 4.72 (dd, J = 10.5 and 5.7 Hz, 1 H, H-4), 4.50 (dt, J = 11.8 and, 3.5 Hz, 1 H, H-3), 4.11-4.22 (m, 2 H, CH₂OH and H-4), 3.98 (td, J = 12.2 and 5.7 Hz, 1 H, H-3a), 3.89 (d, J = 12.2 Hz, 1 H, CH₂OH), 2.15 (s, 1 H, OH). ESI-HRMS: m/z calcd for C₁₀H₁₀N₂O₃ [MH]⁺: 207.0764; found: 207.0759.

10 Boulton JA. McKillop A. In Comprehensive Heterocyclic Chemistry   Vol. 2:  Katrizky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.29-65  

11

Synthesis of Compound 14 from 13.
To a solution of 13 (16.4 mmol, 5.64 g) in THF-MeOH (8:1, 90 mL) at 0 °C NaBH₄ (4.1 mmol, 1.55 g) was added portionwise. The mixture was stirred at 0 °C for further 4 h and then an aq sat. NH₄Cl solution was added. The mixture was extracted with CH₂Cl₂, dried (Na₂SO₄), filtered and evaporated. The crude was purified by short open-column chromatography on silica gel (heptane-EtOAc, 1:1). The residue obtained (0.52 mmol, 1.5 g, 32%) was dissolved in methyl isobutyl ketone (50 mL) and K₂CO₃ (11.7 mmol, 1.62 g) was added. The mixture was stirred at reflux for 4 d and then the solvent was evaporated. The residue was dissolved in CH₂Cl₂, washed with brine, dried (Na₂SO₄), filtered and evaporated. The crude was purified by short open-column chromatography on silica gel (CH₂Cl₂-NH₃ sat. MeOH 19:1) yielding compound 14 as a colorless syrup (2.13 mmol, 0.44 g, 41%).
Representative analytical data for 14: syrup. ¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 8.29 (dd, J = 4.9, 2.0 Hz, 1 H, H-7), 8.12 (dd, J = 7.7, 2.1 Hz, 1 H, H-9), 7.07 (dd, J = 7.7 and 4.9 Hz, 1 H, H-8), 4.79 (dd, J = 10.7 and 5.9 Hz, 1 H, H-4), 4.47 (dt, J = 11.8 and 4.1 Hz, 1 H, H-3), 4.28 (dd, J = 12.5 and 10.7 Hz, 1 H, H-4), 3.85-4.03 (m, 3 H, CH₂OH and H-3a), 3.26 (s, 1 H, OH). ESI-HRMS: m/z calcd for C₁₀H₁₀N₂O₃ [MH]⁺: 207.0764; found: 207.0769.