Unexpected formation of 1,2‐dihydro‐2‐azolyl‐and azinylisoquinolines by the reduction of the corresponding isoquinolinium salts with sodium borohydride in methanol

Abstract

Dedicated to Professor Josef Michl on the occasion of his 65 th birthdayThe reduction of different 2-azolyl-and azinylisoquinolinium salts with sodium borohydride in methanol was studied. Surprisingly, contrary to what is found in the literature 1,2-dihydroisoquinoline derivatives were obtained. Their formation was attributed to the electron withdrawing character of the heterocyclic ring in position 2 of the isoquinolinium moiety. This was corroborated by synthesis and reduction of differently substituted 2-phenyl-and 2-methylisoquinolinium salts. Recently, we have reported on the synthesis of 2-(pyra- [1,2] by the reaction of ortho-acylphenylacetones (1) or the pyrylium salts (1a) formed from them with perchloric acid and the corresponding aminoazoles (2) (Scheme 1).Some of these derivatives moderately but rather selectively inhibited the 5HT 7 receptors showing promising CNS activity. To help them to penetrate through bloodbrain barrier we decided to remove their ionic character by reduction.It was known [3,4] that the isoquinolinium salts (4) were reduced with sodium borohydride in protic solvents like water, methanol, ethanol, etc., to 1,2,3,4-tetrahydroisoquinolines (5) while in aprotic solvents like anhydrous pyridine or dimethylformamide to 1,2-dihydroisoquinolines (6) (Scheme 2). However, electron withdrawing groups in position 3 [5,6] or 4 [7,8] of the isoquionolinium moiety stopped the reduction at the 1,2-dihydroisoquinoline (6) stage even in protic solvents like methanol or ethanol.Surprisingly, when reducing the 6,7-dialkoxy-3-methyl-1-R-2-(5-substituted-1,2,4-triazol-3-yl)isoquinolinium chlorides (3a, A = N, B = C-R", D = NH) with excess of sodium borohydride in methanol only the corresponding 1,2-dihydroisoquinolines 8a (A = N, B = C-R", D = NH) were formed in good yield (see Table I, for their spectral data see Table II) (Scheme 3).To study further this unexpected reaction it was performed also with 2-pyrazolyl-[3b, A = CH, B = C-R"', D = NH], 2-imidazolyl-[3c, A = NH, B = D = CH] and 2-tetrazolyl-[3d, A = B = N, D = NH] isoquinolinium salts prepared mostly for this purpose (see Table III, for their spectral data see Table IV) yielding again only the corresponding 1,2-dihydro-derivatives 8b (A = CH, B = C-R"', D = NH), 8c (A = NH, B = D = CH) and 8d (A = B = N, D = NH), respectively (see Table I, for their spectral data see Table II) (Scheme 4).To extend the scope of this unusual reduction it was performed also with azinyl-, namely the 3-pyridyl-(9a, E = G Nov-Dec 2004915

Synthesis of Tetrahydroisoquinolines via Cascade Reductive Amination of Isochromenylium Tetrafluoroborate with Primary Amines

“…Here, the base potassium carbonate was used to neutralize HBF 4 , the acid produced in this reaction. According to our initial analysis and to the previous report, 15 this reaction might finally give the dihydroisoquinoline derivative 1¢ (Scheme 2a). The ICTB 1a is thought to undergo an insertion reaction with amine 2i, providing an N-aryl isoquinolinium salt.…”

“…14 Prauda and coworkers also showed that some N-aryl isoquinolinium salts could be reduced with sodium borohydride in protic solvents to afford dihydroisoquinolines (Scheme 1b). 15 These studies suggested to us that ICTBs (1) might be able to react with amines, generating isoquinoline derivatives through similar addition/reductive-opening/cyclization mechanisms. Following such an idea, we explored the 'formal' one-step transformations of ICTBs into nitrogenous heterocycles, which would be of value in the synthesis of many biologically important alkaloids.…”

“…Subsequent ring-opening, followed by sodium cyanoborohydride mediated reduction provides the secondary amine E. Intramolecular enamine cyclization of E and reductive amination mediated by sodium cyanoborohydride finally provides the tetrahydroisoquinoline product 4i. In this reaction, it is believed that the N-aryl isoquinolinium intermediate 15 was not formed.…”

“…Scheme 1 (a) Reaction of azaphilone with primary amines, and (b) reduction of N-aryl isoquinolinium salts with sodium borohydride Clearly, reaction of ITCB 1a with amine 2i did not followed the previously known process involving an N-aryl isoquinolinium intermediate (Scheme 1b and Scheme 2a). 15 According to a mechanistic analysis, the stronger reducing power of sodium borohydride is thought to be a major reason for the production of the unexpected amino alcohol 3 rather than isoquinoline derivatives 1¢. To overcome such problems, use of a weaker reducing agent, sodium cyanoborohydride, was then considered (Scheme 3).…”

Redox initiated cationic polymerization: Silane‐N‐aryl heteroaromatic onium salt redox couples

“…The reduction of 2‐phenylisoquinolinium salts by silanes takes place in an analogous fashion (eq 8). Previous work22–24 has established that attack by nucleophiles and hydride reducing agents occurs at the 1‐position in these compounds. This suggests 17 as the organic product of the reduction of 16 .…”