Wiley InterScience Backfile Collection 1832-2000
Chemistry and Pharmacology
Oxidative Aryl-Aryl-Coupling of 6,6′,7,7′-Tetramethoxy-1,1′,2,2′,3,3′,4,4′-octahydro-1,1′-biisoquinoline DerivativesWe describe the synthesis of 2 by intramolecular oxidative coupling of 1, 1′-biisoquinoline derivatives 1 (Scheme 1). This heterocyclic system can be considered as a union of two apomorphine molecules and may thus exhibit dopaminergic activity. - The readily available tetrahydrobiisoquinoline 6 was methylated to 11 (Scheme 4) and reduced (with NaBH3CN) to rac-7 and (catalytically) to meso-7 (Scheme 3). Reduction of 11 with NaBH4 and of the biurethane rac-9 with LiAlH4/AlCl3 afforded meso- and rac-10, respectively (Scheme 4). Demethylation of 6, meso-10, meso- and rac-7 led to 12, meso-14, meso- and rac-13, respectively (Scheme 5). The latter two phenols were converted with chloroformic ester to the hexaethoxycarbonyl derivatives meso- and rac-15 and subsequently saponified to the biurethanes meso- and rac-16, respectively (Scheme 5). - In order to assure proximity of the two aromatic rings, the ethano-bridged derivatives meso- and rac-18 were prepared by condensing meso- and rac-7 with oxalic ester and reducing the oxalyl derivatives meso- and rac-17 with LiAlH4/AlCl3, respectively (Scheme 6). The 1H-NMR, spectra at different temperatures showed that rac-18 populated two conformers but rac-17 only one, all with C2-symmetry, and that meso-17 as well as meso-18 populated two enantiomeric conformers with C1-symmetry. Whereas both oxalyl derivatives 17 were fairly rigid due to the two amide groupings, the ethano derivatives 18 exhibited coalescence temperatures of -20 and 30°. - The intramolecular coupling of the two aromatic rings was successful under ‘non-phenolic oxidative’ conditions with the tetramethoxy derivatives 7, 10 and 18, the rac-isomers leading to the desired dibenzophenanthrolines, the meso-isomers, however, mostly to dienones (Scheme 9): With VOF3 and FSO3H in CF3COOH/CH2Cl2 rac-7 was converted to rac-19, rac-18 to rac-21 and rac-10 to a mixture of rac-20 and the dienone 23b of the morphinane type. Under the same conditions meso-10 was transformed to the dienone 23a of the morphinane type, whereas meso-18 yielded the dienone 24 of the neospirine type, both in lower yields. The analysis of the spectral data of the six coupling products offers evidence for their structures. With the demethylation of rac-20 and rac-21 to rac-25 and rac-26, respectively, the synthetic goal of the work was reached, but only in the rac-series (Scheme 10). - In the course of this work two cleavages of octahydro-1,1′-biisoquinolines at the C(1), C(1′)-bond were observed: (1) The biurethanes 9 and 16 in both the meso- and rac-series reacted with oxygen in CF3COOH solution to give the 3,4-dihydroisoquinolinium salts 27 and 28; the latter was deprotonated to the quinomethide 30 (Scheme 11). (2) Under the Clarke-Eschweiler reductive-methylation conditions meso- and rac-7 were cleaved to the tetrahydroisoquinoline derivative 32.
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