2.7.2. Azido Derivatives

In addition to the obtained ester derivatives, it was decided to install a triazole scaffold due to its presence in clinically used drugs, with a range of pharmacological activities and ability to enhance solubility [29–31]. As a preliminary example of triazole derivatised arctigenin, the simple 4-phenyl-1*H*-1,2,3-triazole moiety was accessed through a coppercatalysed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) click reaction between azidecontaining arctigenin analogue **29** and phenylacetylene.

Azide **29** was afforded through a two-step approach of mesylation and subsequent displacement using sodium azide, affording azide **29** in 78% yield over two steps (Scheme 7).

This process also saw formation of a minor alkyl chloride side product **30** through halide displacement.

**Scheme 7.** Synthesis of nitrogen-containing derivatives. Reagents and conditions: (**i**) MsCl (1.5 equiv.), Et3N (1.4 equiv.), CH2Cl2, 0 ◦C to rt, 2.5 h, **31**; (**ii**) NaN3 (3.8 equiv.), DMF, 85–100 ◦C, 27 h, **29** 78% (two steps) and **30** 25% (two steps); (**iii**) phenylacetylene (1.5 equiv.), Cu2SO4.5H2O (0.16 equiv.), sodium L-ascorbate (0.2 equiv.), MeCN, rt, 4 days, **32** 74%; (**iv**) Pd/C (10% *w*/*w*), H2, EtOAc, rt, 5 days, **33** 29%.

The reaction of azide **29** and phenylacetylene was achieved using sodium ascorbate and copper sulfate pentahydrate in acetonitrile and after four days obtained the 1,4-disubstituted triazole **32** in 74% yield (Scheme 7).

Chloride **30** was stable to catalytic hydrogenation conditions and the benzyl ether removed cleanly through hydrogenolysis to give **33** in 29% yield. However, hydrogenation of triazole **32** was found to be surprisingly difficult and the desired phenol could not be obtained even after using a variety of conditions.
