*3.7. Generation of Compounds 2 and 3 Using the Free Base of Papaverine (1b)*

The free base of papaverine (**1b**, 33.9 mg, 0.1 mmol) was dissolved in CH2Cl2/H2O or DMSO/H2O (2.5:1, 100 μL:40 μL) before the addition of the (CF3SO2)2Zn (198.9 mg, 0.6 mmol) at room temperature. Where TFA was used, 7.7 μL (0.1 mmol) was added to the reaction while stirring. The mixture was cooled to 0 ◦C before TBHP (40 μL, 0.6 mmol) was added, after which time, the stirred mixture was slowly warmed to room temperature over 16 h. The crude reaction product was dried under N2 and pre-adsorbed to NH2-bonded silica (≈1 g) overnight before being subjected to identical NH2 semi-preparative HPLC conditions, which are described above. Reaction conditions and yields for these free base reactions can be found in Table S71.

## **4. Conclusions**

The papaverine scaffold reacted with (CF3SO2)2Zn and TBHP to give dimethoxybenzyl ring-substituted products. With other sulfinates, however, the products featured substitution on the isoquinoline ring. The use of nucleophilic radical precursors, such as zinc isopropylsulfinate, resulted in the replacement of the 3,4-dimethoxybenzyl substituent as the major reaction. A mechanism was suggested for this unusual radical replacement reaction. Despite the fact that the papaverine scaffold was a poor substrate for DiversinateTM chemistry resulting in low yields, we were able to prepare a small library of ten papaverine derivatives (including seven new compounds), some of which would be difficult to prepare by other means. Oxidizing the scaffold to papaverine *N*-oxide had no significant impact on the DiversinateTM yield or selectivity. To the best of our knowledge, these are the first examples of the derivatization of a benzylisoquinoline using DiversinateTM C–H functionalization chemistry. This unique library has been added to the Davis open-access natural product-based library for future drug discovery and chemical biology evaluations [41].

**Supplementary Materials:** The following are available online: 1D/2D NMR spectra for compounds **1**–**12** and DiversinateTM optimization conditions on papaverine HCl salt and papaverine free base.

**Author Contributions:** R.A.D. and F.A.E. conceived, designed, and conceptualized the study. F.A.E. collected the data and literature for the manuscript and performed the experiments. R.A.D. and M.J.C. supervised the study. R.A.D., M.J.C., I.D.J. and F.A.E. wrote the manuscript and all authors reviewed the manuscript. All authors have read and approved the final version of the manuscript.

**Funding:** The authors acknowledge the National Health and Medical Research Council (grant APP1024314 to R.A.D.), the Australian Research Council for support towards NMR and MS equipment (grants LE0668477, LE140100119, and LE0237908), and financial support (grant LP120200339 to R.A.D.).

**Acknowledgments:** F.A.E. thanks Griffith University for two Ph.D. scholarships, the Griffith University Postgraduate Research Scholarship and the Griffith University International Postgraduate Research Scholarship.

**Conflicts of Interest:** The authors declare no conflict of interest.
