Synthesis of 1-Benzyl-1,2,3,4-Tetrahydroisoquinoline, Part I: Grignard Synthesis of 1-(Substitutedbenzyl)-1,2,3,4-Tetrahydroisoquinoline Models with Potential Antibacterial Activity

Yusuf M. Al-Hiari, Bassam A. Sweileh, Ashok K. Shakya, Ghassan Abu Sheikha, Sabah I. Almuhtaseb

Abstract


Benzyl tetrahydroisoquinoline alkaloids have interesting biological activity. This work aims at investigating Grignard conditions for the preparation of models of 1-(substitutedbenzyl)-1,2,3,4-tetrahydroisoquinoline and to investigate their biological activity. The head 3,4-dihydroisoquinoline (3a) was coupled to selected substituted benzyl chloride tails (4a-g) at carbon 1 of the tetrahydroisoquinoline unit, utilizing different Grignard conditions. Thorough investigation proved that the best conditions were to stir a mixture of magnesium turnings, iodine crystals, few drops of 1,2-dibromo ethane in THF and the substituted benzyl chloride tail at –10°C, followed by adding 3a in THF at –80°C. These conditions worked successfully for the preparation of benzyl-tetrahydroisoquinolines 5a-d with acceptable yields (62-86%). The substituted tails benzyloxybenzyl chloride 4f and 4-hydroxybenzyl chloride 4e were added under the same conditions but lower temperatures, furnishing benzyl tetrahydroisoquinolines 5e and 5f in low yields (< 8%). An alternative strategy based on lithiation of N-benzoyl-1,2,3,4-tetrahydroisoquinoline 13 followed by alkylation of the selected tails produced 5e and 5f with satisfactory yields upon hydrolysis of 16; 5e (82%) and 5f (60%). All products and intermediates were isolated, purified and their structure confirmed using NMR, IR and MS techniques. The antibacterial activity against tetracycline resistant MRSA revealed that some compounds were identified as being of potential interest. In particular, compounds 9 (42%), 5e (82%) and 16 (71%) showed interesting antibacterial activity with MIC ranges of 10 to 64 mg/ml. In conclusion, this research was successful in preparing 1-substituted benzyl models of the tetrahydroisoquinoline nucleus. Such models can be good candidates for further biological activity screening tests.

Keywords


Tetrahydroisoquinolines, Benzyl tetrahydroisoquinolines, Grignard reaction, Antibacterial properties, MRSA

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