Synthesis of phenanthridines via palladium-catalyzed picolinamide-directed sequential C–H functionalization

Summary We report a new synthesis of phenanthridines based on palladium-catalyzed picolinamide-directed sequential C–H functionalization reactions starting from readily available benzylamine and aryl iodide precursors. Under the catalysis of Pd(OAc)2, the ortho-C–H bond of benzylpicolinamides is first arylated with an aryl iodide. The resulting biaryl compound is then subjected to palladium-catalyzed picolinamide-directed intramolecular dehydrogenative C–H amination with PhI(OAc)2 oxidant to form the corresponding cyclized dihydrophenanthridines. The benzylic position of these dihydrophenanthridines could be further oxidized with Cu(OAc)2, removing the picolinamide group and providing phenathridine products. The cyclization and oxidation could be carried out in a single step and afford phenathridines in moderate to good yields.

(PA)-directed C-H functionalization reactions beginning from easily accessible PA-protected benzylamine and aryl iodide precursors.

Results and Discussion
New synthetic strategy for phenanthridine compounds. The picolinamide (PA) group has been shown to be an excellent directing group for a range of Pd-catalyzed C-H functionalization reactions [26][27][28][29][30][31][32][33][34][35]. In 2005, the Daugulis laboratory first reported that the ortho-C(sp 2 )−H bond of benzylpicolinamides could be arylated with aryl iodides under Ag-promoted Pd-catalyzed conditions [26]. In 2012, our laboratory [28] as well as that of Daugulis [27] independently reported that picolinamide substrates can undergo intramolecular dehydrogenative C-H amination reactions to afford medium-sized N-heterocycles under the catalysis of Pd(OAc) 2 with PhI(OAc) 2 oxidant. These discoveries led us to explore whether we could develop a new strategy for synthesizing phenanthridines. As outlined in Scheme 1B, we envisioned that ortho-arylated benzylamine picolinamides could undergo an intramolecular amination at the ortho ε-C-H position of the newly installed arene group to form cyclized dihydrophenanthridines, which could be further converted to phenanthridine products under oxidative conditions. Ideally, we hoped to perform both the intramolecular C-H amination and subsequent oxidation in a single step [36].
Arylation of 2-methoxybenzyl picolinamide 1 with 4-iodoanisole (2) under various conditions. We commenced the study by investigating the arylation of 2-methoxybenzyl picolinamide 1 with 4-iodoanisole (2) under various conditions (Table 1) to form our desired arylated product 3. Our initial attempt under the original Pd(OAc) 2 -catalyzed AgOAcpromoted solvent-free condition afforded the desired arylated product 3 in good yield ( Table 1, entry 1). This method, however, required the use of expensive silver salt as an additive and high reaction temperature (150 °C). We next sought to replace the silver salts with cheaper reagents and lower the reaction temperature [12]. Not surprisingly, the arylation yield dropped significantly when the reaction was performed in toluene solvent at 120 °C (  To our delight, the desired arylation reaction was largely restored with the application of 2 equiv of K 2 CO 3 at 120 °C for 24 h (Table 1, entry 5). Furthermore, an excellent yield was obtained when K 2 CO 3 was replaced with KHCO 3 and 0.3 equiv of PivOH was applied (Table 1, entry 7). The most effective carboxylate ligand and solvent was found to be PivOH and toluene, respectively.
The determination of the scope of this reaction with benzylpicolinamide and aryl iodide substrates. With the optimized conditions in hand, we next explored the scope of benzylpicolinamide and aryl iodide substrates ( Figure 1). The electronic properties of benzylpicolinamide and aryl iodides had little influence on the reactivity, as benzylpicolinamide and aryl iodide substrates bearing electron-donating and withdrawing substituents react in good yields (3, 8, and 12). Significantly decreased arylation yield was observed for ortho-substituted aryl iodides (e.g., 9). The sterics of the benzylpicolinamides is also important for the regioselectivity of the arylation reaction. For instance, the less hindered ortho position is preferentially arylated (e.g., 14) when a meta substitutent is present on the benzylpicolinamide. Aryl bromides are much less reactive compared with aryl iodide substrates 4. This is in accordance with results on the Pd-catalyzed PA-directed arylation of more inert C(sp 3 )−H bonds [29].
Cyclization of biaryl compounds to form dihydrophenanthridines. Next, we investigated the cyclization of biaryl compounds to form dihydrophenanthridines via Pd-catalyzed intramolecular dehydrogenative amination of ε-C(sp 2 )-H bonds [37][38][39][40][41][42][43][44][45]. To our delight, treatment of 3 in the presence of 5 mol % of Pd(OAc) 2 and 2 equiv of PhI(OAc) 2 in toluene at 120 °C for 24 h gave the desired dihydrophenanthridine 16 in good yield ( Table 2, entry 1). In addition, a further oxidized phenanthridine 17 was obtained as a side product. Compound 17 is presumably generated through the PhI(OAc) 2 -mediated oxidation of the benzylic C-H bond to form a phenanthridinium intermediate 18, which then undergoes a removal of the PA group. Encouraged by these observations, we proceeded to explore whether the cyclization and oxidation steps can be performed in one step to give the phenanthridines in a shorter procedure. A variety of oxidants, such as 1,4-benzoquinone (BQ), KMnO 4 , ceric ammonium nitrate (CAN), and copper salts were examined [46]. The combination of PhI(OAc) 2 (2 equiv) and Cu(OAc) 2 (2 equiv) afforded the phenanthridine product 17 in highest yield ( Extension of the cyclization-oxidation step to other arylated picolinamide substrates. The coupled cyclization-oxidation step detailed above was then used to synthesize phenanthridines from other arylated picolinamide substrates ( Figure 2). In general, electron-rich arene motifs, installed by C-H arylation, gave a higher yield of phenanthridine products; electron-deficient substrates provide a lower yield. For instance, substrate 8 with a para-nitro group failed to give any cyclized product under the standard conditions. Substrates with moderately electron-withdrawing groups, such as 20 bearing a paraester group, reacted in moderate yield. The electronic properties of the benzylpicolinamide scaffold had much less influence on the reaction. For example, product 22 bearing an ortho-CF 3 substituent was obtained in 51% yield. Finally, it is noteworthy that all of the above phenanthridine products show intense blue fluorescence. We expect our synthetic strategy will afford access to phenanthridines bearing varied substitution patterns, enabling applications in biology and materials science.

Conclusion
In summary, we have developed a readily applicable two-step method for the synthesis of phenanthridines from easily accessible benzylamine picolinamides and aryl iodides. In the first step, an improved protocol allows us to carry out the Pd-catalyzed PA-directed C-H arylation reaction without the use of expensive silver additives. In the second step, application of PhI(OAc) 2 and Cu(OAc) 2 oxidant under the catalysis of  Pd(OAc) 2 affords phenanthridines in moderate to good yields. Applications of this method to the synthesis of more complex phenanthridines with novel photophysical properties are currently underway.

Experimental
General conditions: All commercial materials were used as received unless otherwise noted. All solvents were obtained from a JC Meyer solvent dispensing system and used without further purification. Flash chromatography was performed using 230-400 mesh SiliaFlash 60 ® silica gel (Silicycle Inc.