Abstract
A simple procedure for the synthesis of 8-fluoro-3,4-dihydroisoquinoline is described below, based on a directed ortho-lithiation reaction. This key intermediate was then applied in various transformations. Fluorine–amine exchange afforded the corresponding 8-amino-3,4-dihydroisoquinolines, suitable starting compounds for the synthesis of 1-substituted 8-amino-tetrahydroisoquinolines. On the other hand, reduction and alkylation reactions of 8-fluoro-3,4-dihydroisoquinoline led to novel 1,2,3,4-tetrahydroisoquinoline derivatives that can be used as building blocks in the synthesis of potential central nervous system drug candidates.
Highlights
Isoquinolines and their partly saturated congeners constitute an important class of natural and synthetic compounds exhibiting biological activity.N-Acylated 1,8-disubstituted 1,2,3,4-tetrahydroisoquinolines 1 [1] and 2 [2] (Figure 1) proved to be potent calcium channel blockers for the treatment of chronic pain
The C-1 position has to be activated by quaternization with benzyl bromide (12) before treatment with with the appropriate Grignard reagent to give 1-aryl derivative 13
The seemingly shorter synthesis starting from 2-bromobenzaldehyde (Scheme 4) does not ensure an alternative, since Pomeranz–Fritsch cyclization of Schiff base 21 gives very low, irreproducible yields [20]
Summary
When starting from 8-fluoroisoquinoline (11, Scheme 3), a similar introduction of the substituent into position 1 is more complicated, as demonstrated by the synthesis of compound 2 (see Figure 1) [2]. The C-1 position has to be activated by quaternization with benzyl bromide (12) before treatment. The C-1 position has to be activated by quaternization with benzyl bromide (12) before treatment with with the appropriate Grignard reagent to give 1-aryl derivative 13. Reduction of the hetero ring, the appropriate Grignard reagent to give 1-aryl derivative 13. Reduction of the hetero ring, of 11 introduction of the N-substituent, leads to target compound 2. Followed by removal of the benzyl group to furnish tetrahydro congener 14 and subsequent introduction of the N-substituent, leads to target compound 2
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