A NEW APPROACH TO THE SYNTHESIS OF SUBSTITUTED PHENAZINES VIA PALLADIUM-CATALYZED ARYL LIGATION(i.)

The ligation of aromatic rings represents an important tool for the synthesis of molecules of increasing complexity,ii with important applications in the synthesis of natural and unnatural products. We describe here the implementation of such a strategy for the preparation of substituted phenazines,iii leading to the synthesis of disubstituted heterocycles that cannot be otherwise prepared with comparable levels of efficiency (Figure 1). Figure 1 Regiochemistry of Synthesis of Disubstituted Phenazines Previous efforts by Beifussiv and Senanayakev have suggested that such a process should be possible, although with only single examples in unoptimized yields, both of which employ the highly pyrophoric ligand tri-t-butyl phosphine. We report herein the optimization of this process and its implementation as a method of choice for the synthesis of unsymmetrically disubstituted phenazines. We further describe the application of this reaction sequence to the aryl ligation of two molecules of tryptophan to generate the previously unreported heterocyclic ring system 1,7-dihydrodipyrrolo-[2,3-b:2′,3′-i]phenazine, a highly fluorescent pentacyclic ring system. We report herein that a series of bromoanilines that are substituted with either electron-donating or electron-withdrawing groups can be regioselectively converted to the corresponding disubstituted phenazines in good yields using BINAP or other crystalline phosphine ligands in lieu of tri-t-butyl phosphine (Table 1). Using the Buchwald C-N Ligand Kit available from Strem Chemicals, a series of phosphines were surveyed, and the two ligands that afforded the highest yields are presented in the Table for each substrate, illustrating the absence of a single optimal phosphine ligand in this reaction. Similar results were observed with the 2-chloroaniline (64% yield) although the corresponding triflates resulted only in oxygen to nitrogen triflate migration in lieu of the desired coupling reaction. The last entry in Table 1 is particularly notable as, even though the observed yield is moderate, none of the desired phenazine product was observed with BINAP.vi Table 1 The Effect of Phosphine Ligand on Phenazine Yield We next examined the reaction of more complex aminoaromatics derived from amino acid precursors, as outlined in Figure 2. Aryl ligation of tryptophan using this strategy could lead to the previously undescribed dihydrodipyrrolophenazine ring system shown in 13. Toward that end, dimerization of 10,vii leads to the formation of the corresponding phenazine in 51% yield. However, all attempts to convert 11 to the ring-opened product under the reaction conditions described by Hino and coworkers7 led to none of the desired product 13. Direct dimerization of the N-Boc tryptophan 12 produced the desired ring system 15 in 49% yield. The UV spectrum of 13 was notable for a λmax of 406 nm, and the fluorescence spectrum of 13 featured a λem of 538 nm, with a Stokes’ shift of 132. Figure 2 Synthesis of Complex Phenazines The analogous reaction of the phenylalanine-derived substrate 14 afforded the corresponding phenazine 15 in 63% yield. A further example of the regiochemical control that is possible with this phenazine construction strategy is the formation of 17, albeit in 40% yield, from 16, without formation of the corresponding dibenzo[a,j]phenazine, a result that would not be possible using the more classical approaches to the synthesis of substituted phenazines.viii Finally, we demonstrate that this strategy is not limited to dimerization. By judicious choice of substituents on the aniline ring, i.e., by exploiting the decreased reactivity of anilines substituted with electron-withdrawing groups, we have demonstrated that the reaction of 18 with 2-bromoaniline leads to the formation of 19 in 65% yield. The application of this methodology to the synthesis of diverse substituted phenazines is currently underway in our laboratory and our results will be reported in due course.