Synthesis of Phenanthridine by Palladium Catalyzed Suzuki Coupling and Condensation Reaction

Transition metal catalyzed cross-coupling reactions such as Suzuki-Miyaura, Heck, Stille, Hiyama, Negishi, and Sonogashira reactions are likely to be the most power tool for the formation of C-C bonds for the past four decades. All these reactions have shown their widespread applicability ranging from academic area to research. Some of the reactions have also been applied in pharmaceuticals, agrochemicals, and fine material industries. The Suzuki-Miayura cross coupling was remained the most attractive alternative for C-C bonds formation since its discovery in 1979. The wide range of applicability of this reaction is largely attributed to mild reaction conditions, broad range of functional group tolerance, easy access to organo-boron reagents, and their stability under air and moisture. Furthermore, boron compounds show low toxicity and easy to separate boron from the reaction mixtures.


Introduction
Transition metal catalyzed cross-coupling reactions such as Suzuki-Miyaura 1 , Heck 2-10 , Stille 11 , Hiyama, 12 Negishi 13 , and Sonogashira reactions are likely to be the most power tool for the formation of C-C bonds for the past four decades. All these reactions have shown their widespread applicability ranging from academic area to research. Some of the reactions have also been applied in pharmaceuticals, agrochemicals, and fine material industries. The Suzuki-Miayura cross coupling was remained the most attractive alternative for C-C bonds formation since its discovery in 1979. The wide range of applicability of this reaction is largely attributed to mild reaction conditions, broad range of functional group tolerance, easy access to organo-boron reagents, and their stability under air and moisture. Furthermore, boron compounds show low toxicity and easy to separate boron from the reaction mixtures.

Bioactivity and natural occurrences
Phenanthridines and Benzo[c]phenanthridines are prevalent in a large number of natural and unnatural bioactive molecules exhibiting important pharmacological activities and applications, such as antibacterial, antiprotozoal, and anticancer agents. A well known member of this class of compound is ethidium (3.3), a common DNA intercalator and stain.
Representative alkaloids of this kind with promising pharmacological potential are nitidine  Because of great importance of these compounds in biology and medicine, shorter and high yielding synthetic methodologies are of great interest in synthetic organic chemistry as isolation from natural sources described is less than 1%.
The in situ generated benzyne from benzenediazonium-2-carboxylate 3.7 underwent a [4+2] cycloaddition reaction with the imine formed from aromatic amine and aldehyde to give dihydrophenanthridine. Finally, dehydrogenation in the reaction medium gave the 6-arylated phenanthridine 3.10 in quantitative yields.      In our continuous effort in finding the shorter and economic synthetic methods via palladium catalysis, we have achieved a synthesis of phenanthridines and its analogs in this chapter. Our aim was to find out one step method for the synthesis of phenanthridine. We envisioned that Suzuki coupling between 3.36 and 3.37 would be very effective for the construction of phenanathridine 3.38 in one-pot (Scheme 3.11).

Results and Discussions
We report a one-pot strategy to achieve phenanthridine 3.38 and analogous derivatives 3.41 Further increase of reaction temperature and changing the solvent to DMSO has no effect on the reaction. So, the set of optimal reaction conditions were finalized to be Pd(OAc)2 (5 mol %), PPh3 (0.25 equiv.), Cs2CO3 (1.5 equiv.), in DMA (3 mL), at 90 °C , for 3 h (Table 3.1, entry 10). 3.37a-f in good yields. The results in the Table 3.2 shows that this methodology is well tolerated both the electron-donation and electron with-drawing functionalities such as, nitro, methyl, methoxy group in the coupling partner 3.7.    b) Isolated yields.
The cyclization reaction was believed to follow the sequential steps of Suzuki coupling followed by condensation. The Suzuki coupling occurs first between the coupling partners to produce the intermediate I which then undergoes intramolecular cyclization to afford the phenanthridine II. In contrast, if the condensation is to be occurred first it would result the more stable trans-imine III from which intramolecular coupling is quite impossible as the two functional groups are far apart (Fig 3.3). Evidence in support of our proposal comes from that fact no imine was isolated during the reaction course.

Conclusion
In conclusion a simple and efficient method for the synthesis of different substituted phenanthridine and it higher analogues benzo[k] and benzo[i] derivatives have been developed. Our synthetic strategy is a general one with tolerability to a variety of substituent and gave highly substituted phenanthridines in quite good yields from very cheap starting materials under mild reaction conditions. We anticipate that our methodology could be applicable to synthesize phenanthridine natural products of important medicinal value 5,8,10, .