Removal of the Pyrrolidine Substituent by Dehydrogenation of 4‐Pyrrolidin‐2‐yl‐3,4‐dihydro‐and 1,2,3,4‐tetrahydroisoquinolines

Abstract

Pyrrolidin-2-yl-groups located at C-4 of 3,4-dihydro-or 1,2,3,4-tetrahydroisoquinolines, respectively, are lost in the course of dehydrogenation of these isoquinoline derivatives. However, acyclically substituted isoquinolines, hydrogenated in ring B, 2-benzyl-4-( 1 -dimethylaminoethyl)-1.2.3.4-tetrahydroisoquinoline, e.g., show loss of the amine group only by benzylic cleavage, affording 4-ethylisoquinoline. Scope and limitation of this reaction are determined using specifically substituted isoquinolines.In the context of the removal of a N-methylpyrrolidine group by dehydrogenation from C-4 of the 3.4dihydroisoquinoline skeleton in the course of the synthesis of the papaveraceae alkaloid macrostomine (1)') we have reported on the dehydrogenation of simple 3,4-dihydro-and 1.2.3.4-tetrahydroisoquinolines with pyrroline-and pyrrolidine increments at C-4: besides analogous losses we observed the expected dehydrogenation reaction (Scheme 3 in lit?)) and rearrangements (Scheme 4 in lit?))*).Here we describe experiments performed in order to get some insight into scope and limitation of this abnormality. Results of Dehydrogenation ExperimentsThese experiments were performed under standard conditions: 10 % Pd/C, tetraline, 190" -210°C N2, 1 -2 h.Whilst the l-methyl-4-(2,5-dihydro-N-rnethylpyrrol-2-y1)-3,4-dihydroisoquinoline 2 is nicely aromatized in the pyrroline-as well as in the dihydroisoquinoline-moiety (Scheme 5 in Lit.')), the 3,4-dihydro-SH-pyrrole group and the 3,4,5,6-tetrahydropyridine increment at C-4 of the (aromatic) isoquinolines 3 and 4, respectively, remain unchanged.This holds true also for the pertinent sec amines 5 and 6, and also the corresponding N-methylated pyrrolidine-and piperidine-derivatives 7 and 8 are not dehydrogenated. In all theses cases the heterocyclic ring at C-4 of the isoquinoline systems is not split off. As already observed by Seebach3) in his synthesis of macrostomine (l), the loss of the pyrrolidine increment is prevented by N-formylation: cpds. a) the non-bonding electron pair at the N-atom of the attached ring is a prerequisite for this cleavage. Here only the tetrahydroisoquinoline system is dehydrogenated.b) the loss of the fully hydrogenated N-heterocycle is synchronous with the dehydrogenation of the 3,4-dihydro-or 1,2,3,4-tetrahydroisoquinoline nucleus.In order to check point b) we have prepared cpd. 11 with two substituents at C-4. Here, the 3,4-dihydroisoquinoline system as well as the N-methylpyrrolidine group should survive the dehydrogenation conditions, because we expected aromatization not to occur. This assumption, however, turned out to be wrong: there was loss of the pyrrolidine increment in 11 (for the fate of this group cf. lit.2)), and the 3,4-dihydroisoquinoline system was aromatized affording the 1,4-dimethylisoquinoline 12. Curiously enough this reaction took place even without Pd as a catalyst by thermal cleavage only. So it seemed reasonable to assume that gain of aromatization energy is the driving force for this cleavage, but this assumption is disput...