Synthesis of pyrrolo[3,2-a]phenazines from 5-nitroindoles and anilines

Abstract Anilines react with 5-nitroindoles in the presence of t-BuOK in N,N-dimethylformamide (DMF) to form 5-nitroso-4-arylaminoindoles that in turn when treated with N,O-bis(trimethylsilyl)acetamide cyclize to pyrrolo[3,2-a]phenazines. In an alternative approach pyrrolo[3,2-a]phenazines are formed from aminoindoles and nitroarenes. Graphical abstract

The classic Wohl-Aue synthesis of phenazines consists in the reaction of anilines with nitroarenes under harsh basic conditions, usually by heating of both starting materials with sodium or potassium hydroxide at 200°C [5]. In recent years we extensively studied nucleophilic aromatic substitution reactions of hydrogen in nitroarenes [11][12][13][14][15]. During these studies we have found that anilines react with nitrobenzene derivatives under mild conditions in the presence of t-BuOK in DMF at -50°C to form 2-nitrosodiphenylamines that in turn upon treatment with acetic acid cyclized to phenazines (Scheme2) [16,17].
Some of these compounds (3b and 3f) proved unstable and thus after isolation without further purification they were used in the next step to form phenazines. The 1 H and 13 C NMR spectra of the obtained nitrosoamines 3 and 7 deserve some comments. In the spectra of some of these compounds we observed broadening of the signals corresponding to the protons and carbon atoms of the nitrososubstituted moiety and thus their full interpretation was troublesome. Such a signal broadening is probably due to a slow rotation of the nitroso group around the C-N bond. A similar phenomenon was observed in the NMR spectra of 2-(alkylamino)-and 2-(arylamino)nitrosobenzenes [27,28].
In our earlier papers we have shown that cyclization of N-(2-nitrosophenyl)anilines to phenazines proceeds satisfactorily in boiling acetic acid [16,17], with K 2 CO 3 in methanol at room temperature [17], or with N,O-bis(trimethylsilyl)acetamide (BSA) [17]. Attempted cyclization of the model nitroso compound 3d in boiling acetic acid was unsuccessful; the starting material was consumed within 90 min (TLC control) but no defined products were obtained. No reaction of 3d was observed in the presence of K 2 CO 3 in methanol. The cyclization of 3d occurs satisfactorily in the presence of BSA in DMF at 80°C giving the expected pyrrolophenazine 4d in good yield. These reaction conditions were adapted to reactions of other 4-(Narylamino)indoles 3. The results are summarized in the Table 1.
In summary, a novel two-step approach to pyrrolophenazines starting from easily available nitroindoles and anilines was developed. In an alternative reaction sequence the pyrrolophenazines can be obtained from nitroarenes and aminoindoles. The simplicity of this approach makes it an interesting alternative to other procedures.

Experimental
All reactions were performed under argon atmosphere. 1 H and 13 C NMR spectra were recorded on Bruker 500 MHz spectrometer (500 MHz for 1 H and 125 MHz for 13 C spectra). Chemical shifts (d) are expressed in ppm referred to TMS, coupling constants in Hertz. Mass spectra (EI, 70 eV) were obtained on an AMD-604 spectrometer. ESI mass spectra were obtained on SYNAPT G2-S HDMS. Merck silica gel 60 F 254 plates were used for TLC. Merck silica gel 60 (230-400 mesh) was used for flash column chromatography.