I want to synthesize an amide using tetrahydroisoquinoline and an unsaturated carboxylic acid which is light sensitive. I tried using DCC as a coupling agent and DCM as the solvent at room temperature, but it didn't work for me. The tetrahydroisoquinoline is in hydrochlorated form.
Do I have to do acid extraction prior to synthesis, or I can use the hydrochlorated form itself? Please suggest a good method along with the conditions for the reaction to be carried out.
A SciFinder search gave 200 or so examples of coupling tetrahydroisoquinoline with an unsaturated carboxylic acid (including benzoic acids and the like). Surprisingly dicyclohexylcarbodiimide (DCC) was not one of the reagents used, although N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) was used in more than 50 cases. Other common amide coupling agents including PyBOP, BOP, HBTU, and HATU were reported. Another related strategy through a mixed carbonate/anhydride by activating the acid with isobutylchloroformate.
I'm not sure if you have to isolate the free base of your amine first, but you should certainly include a base to liberate the active nucleophile. If you haven't tried it yet, add an equivalent of triethylamine or diisopropylethylamine.
Aapptec, a supplier of reagents and building blocks for peptide synthesis, has a nice compilation of the different amide coupling reagents that are used: Aapptec coupling reagents.
