Strategies for the synthesis of tetracyclic diltiazem analogues

Synthesis Reaction of 1a,b with 2-aminothiophenol and sodium ethanolate in ethanol does not give the expected tetracyclic ring systems, but surprisingly the spirocompounds 2 are obtained. A [2+4] cycloaddition of the intermediately formed 1,2-benzoquinone-2-imine-1-thione with the aurone was postulated. Under these conditions the thioaurones 1c,d showed no reaction. After reaction of 1with 2-aminothiophenol and trifluoroacetic acid (TFA) in toluene using a water separator and workup only the educts 1 were recovered. By way of contrast the 6,12-dihydrobenzofuro [2,3-c][1,5] benzothiazepines 3a,b and the 6,12-dihydrobenzothieno [2,3-c][1,5] benzothiazepines 3c,d were obtained in good yield by heating 1a-d in polyphosphoric acid (PPA) under nitrogen. The H-NMR spectra of the isolated tetracycles proved the existence of the enamine form. The opposite tautomeric imine form is found by the carba-analogue indeno[2,3-c][1,5] benzothiazepines. According to the synthesis of diltiazem [6,7] the compounds 3 were treated with 2-chloroethylN,N-dimethylammonium chloride and potassium carbonate in ethyl acetate. The annulated benzofuranes 3a,b were isolated as orange crystals whose UV/Vis spectra were similar to those of the aurones. The H-NMR spectra showed a singlet for a methine proton located on a sphybridized carbon. The signals for a methylene proton don`t fit with a nitrogen-substituted but a sulphur-substituted product. Therefore not the diltiazem-analogues 4a,b but the imino-aurones 5a,b were obtained by S-alkylation and cleavage of the seven membered ring. The annulated benzothiophenes remained stable. Therefore the tetracycles were deprotonated with sodium hydride in dimethylformamide (DMF) and than the basic substituted alkylhalogenide was added. The resulting products were orange red coloured. Refering to the mass and H-NMR spectra instead of alkylation hydrogen sulfide was eliminated by ring contraction yielding the annulated quinolines.