5,6,7,8-Tetrahydro-3-(1-methoxyiminobutyl)-1-methylsulfonylisoquinoline

As part of research programme directed to the synthesis of novel heterocyclic compounds pharmacologically interesting [1] via ring transformation of 1,2,4-triazine derivatives, we synthesized the title compounds 3 via two step process. Starting compounds, 5-(methoxyiminobutyl)-3-(methylsulfanyl)-1,2,4-triazine (1) [2] was easily oxidized under PTC-conditions into the corresponding sulfone 2. The latter compound, as reactive azadiene [3], was subjected in crude form to [4+2]cycloaddition-retro cycloaddition with 1-pyrrolidino-1-cyclohexane as dienophile to give 5,6,7,8-Tetrahydro-3-(1-methoxyiminoethyl)-1-methylsulfonylisoquinoline (3) in 70% yield.

Preparation of 2:

A solution of KMnO₄ (474 mg, 3 mmol) in water 20 ml) was added to a solution of 1 (226 mg, 1 mmol) and Bu₄N⁺Br^- (48 mg, 1.5 mmol) in a mixture of AcOH (1.8 ml, 30 mmol) and benzene (15 ml) during stirring and cooling to 5-10^oC. The reaction was continued at 10^oC for 1-1.5 h, until complete oxidation process was observed with monitoring by TLC (CHCl₃/acetone -50:1). A saturated solution of Na₂S₂O₅ for decoloring, then saturated solution of K₂CO₃ for neutralization were added. The organic layer was separated and water phase was extracted with benzene (3 x 20 ml).

The combined organic layers were washed with water (2 x 20 ml) and dried over MgSO₄. After evaporation of the solvents under reduced pressure to volume of 5 ml, the solution was contained of pure product 2 (TLC monitoring) and was used for next step.

IR (KBr, ν, cm^-1): 3030 (CH_aromat.); 2975, 2850 (CH₃); 1665 (C=N); 1565, 1460, 1395 (aromat. ring); 1335, 1155 (SO₂); 1075 (C-O);

¹H-NMR (CDCl₃, 200 MHz); δ= 9.64 (s, 1 H, CH_aromat.); 4.20 (s, 3 H, CH₃O); 3.45 (s, 3H, CH₃SO₂); 2.90 (t, J= 7.7 Hz, 2 H, H₂CC=N); 1.60 (m, 2 H, H₂CCH₂C=); 1.05 (t, J=7.4 Hz, 3 H, H₃CCH₂).

Preparation of 5,6,7,8-Tetrahydro-3-(1-methoxyiminobutyl)-1-methylsulfonylisoquinoline (3):

To the freshly obtained solution of 2 (1 mmol), was added 1-(N-pyrrolidine)cyclohexene (302 mg, 2 mmol). The reaction mixture was refluxed for 1h until the substrate 2 was disappeared (TLC monitoring: CHCl₃/acetone-50:1). Removal of solvents under reduced pressure and purification of the residue by column chromatography on silica gel (230-400 mesh, Merck type 60) using chloroform/hexane - 3:1 as eluent gave 218 mg (70 %) of 5,6,7,8-tetrahydro-3-(1-methyoxyiminobutyl)-1-methylsulfonylisoquinoline (3) as a white solid after recrystalization from mixture chloroforme/hexane 1:2.

Melting point: 84-85^oC

IR (KBr, ν, cm^-1): 3030 (CH_aromat.); 2975, 2875, 2855 (CH₃, CH₂); 1660 (C=N); 1550, 1460 (aromat. ring); 1340, 1170 (SO₂); 1070 (CH₃O).

¹H-NMR (CDCl₃, 200 MHz): δ= 7.71 (s, 1 H, CH_aromat.); 3.95 (s, 3 H, CH₃O); 3.70 (s, 3 H, CH₃SO₂); 3.16 (t, J=5.5Hz, 2 H, C⁸H₂); 2.83 (t, J=5.7 Hz, 2 H, C⁵H₂); 2.64 (t, J=7.6 Hz, 2 H, CH₂C=N); 1.94-1.76 (m, 4 H, C⁶H₂C⁷H₂); 1.61 (m, 2 H, H₂CCH₃); 0.97 (t, J=7.5 Hz, 3H, H₃CCH₂).

MS (EI), m/z (% rel. int.): 310 (100) [M⁺]; 295 (13); 279 (35); 267 (13); 250 (15); 212 (25); 181 (33).

Elemental Analysis: Calculated for C₁₅H₂₂N₂O₃S: C, 58.04%; H, 7.14%; N, 9.03%. Found: C, 57.88%; H, 7.20%; N, 8.90%.