Free-radical cyclization approach to polyheterocycles containing pyrrole and pyridine rings

A wide range of derivatives with new pyrido[2,1-a]pyrrolo[3,4-c]isoquinoline skeleton was synthesized by free-radical intramolecular cyclization of o-bromophenyl-substituted pyrrolylpyridinium salts using the (TMS)3SiH/AIBN system. The cyclization provides generally good yields of pyrido[2,1-a]pyrrolo[3,4-c]isoquinoline hydrobromides having no additional radical-sensitive substituents. The free bases can be obtained from the synthesized hydrobromides in quantitative yield by basification at room temperature. The selectivity control of intramolecular arylation was achieved by replacing the halogen: the use of 1-(2-(ortho-bromophenyl)-4-(ortho-iodophenyl)pyrrol-3-yl)pyridinium bromide makes it possible to obtain a monocyclization product, and the bicyclization product from the dibromo derivative. The procedure is also applicable to obtain 3-arylpyrido[2,1-a]pyrrolo[3,2-c]isoquinoline derivatives including 2-unsubstituted skeletons that are inaccessible via Pd-catalyzed cyclization.

The use of 1,1'-azobis(cyclohexanecarbonitrile) or Et 3 B as radical reaction initiators instead of AIBN was unsuccessful.
Therefore, the reaction conditions for the free-radical cyclization of salt 1a were further optimized by variation of the mediator/initiator ratio, temperature, reaction time, concentration of 1a, and reagent mixing procedure ( Table 1). The optimal conditions found (entry 8, Table 1), characterized by the use of minimum amounts of reagents, were used to evaluate the substrate scope for the synthesis of compounds 3 ( Table 2). The developed protocol doesn't require column chromatography for purification of target compounds 3 and can be performed in a gram scale.
Pyridinium bromides 1a-l,n-w and iodide 1m were prepared by the reaction of 3-(2-bromophenyl)-2H-azirine (4a) with substituted N-phenacyl pyridinium salts 5a-w according to the published method (Table 2) [14]. The free-radical cyclization tolerates 4-F and 4-Cl substituents in the 2-phenyl ring (Table 2, entries 2,3), whereas the reaction of compound 1d, with a 4-Br substituent in the 2-phenyl ring, led to the formation of a complex mixture of products because of competitive radical reactions. Methyl and methoxy substituents in the 2-phenyl ring ( Table 2, entries 5-9) did not affect the cyclization, whereas the presence of 3-or 4-NO 2 -substituents ( Table 2, entries 10 and 11) led to tarring of the reaction mixtures probably due to par- ticipation of the NO 2 group in side radical reactions. The fact that this result is not related to the electron-withdrawing nature of this substituent follows from the fact that another strong EWG at the position 4, such as cyano, did not interfere with the reaction, and the product was obtained in good yield. (Table 2, entry 12). It is important that the reaction of iodide 1m with 2-pyridyl substituent gave a good yield of the product 3m, which could be used for the preparation of bidentate ligand for metal complexes. Reaction of salts 1 with electron-donating para-substituents (Me, MeO, Me 2 N) in the pyridine ring (1n-p,s) and aryl substituents (1q,r) afforded the corresponding compounds 3 in 51-82% yield ( Table 2, entries [14][15][16][17][18][19]. Heating of isoquinolinium salt 1t with the TTMSS/AIBN system, disappointingly, led to intensive tarring without the for-mation of the cyclization product in even trace amounts. Salts with electron-withdrawing para-substituents in the pyridine ring (1u-w) do not cyclize under used reaction conditions. The reaction of 2H-pyrido[2,1-a]pyrrolo [3,4-c]isoquinolin-4-ium bromides 3 with aq KOH at room temperature gave quantitatively the corresponding bases 6 ( Table 2).
Pyridopyrroloisoquinolinium bromide 8, functionalized with an alkoxycarbonyl group at the C1 position, was also synthesized by the developed approach, starting from azirine 4b (Scheme 3).
Iodo-substituted salt 2 should be more reactive towards cyclization as compared to its bromo-analogue, and this can be used to Encouraged by the above mentioned results we decided to apply the developed methodology for the preparation of pyrido[2,1a]pyrrolo [3,2-c]isoquinoline derivatives A (Scheme 1). The pre-  viously developed Pd-catalyzed protocol for the preparation of these compounds could be used only for arylation of pyrrole N-benzyl protected starting materials C [17]. The deprotection of the product could be performed only with AlCl 3 under harsh conditions and, therefore, cannot be used for the preparation of compounds with acid-sensitive substituents. In addition, the debenzylation of 1-benzyl-3-arylpyrido[2,1-a]pyrrolo [3,2c]isoquinolines A was found to accompany by isomerization to 2-aryl derivatives, and therefore 2-unsubstituted bases A could not be prepared by a Pd-catalyzed procedure [17].
Optimal reaction conditions, found for the preparation of compounds 3 afforded reasonable results for the synthesis of 3-arylsubstituted heteroaromatics 17 ( The structure of 17a was confirmed by XRD-analysis ( Figure 3).
It was found that both salt 17a and base 18a can be isomerized into isomer 19 under heating in the presence of AlCl 3 via migration of the 3-Ph-group into the position 2 (Scheme 6).
Compounds 18a, 19 can be quantitatively N-alkylated by MeI at room temperature and by BnBr at 40 °C (Scheme 7).
A study of photophysical and electrochemical properties of compounds 3 is in progress and will be published elsewhere.

Conclusion
A wide range of derivatives with new pyrido[2,1-a]pyrrolo [3,4c]isoquinoline skeleton was synthesized by free-radical intramolecular cyclization of o-bromophenyl-substituted pyrrolylpyridinium salts using the TTMSS/AIBN system. The cyclization provides generally good yields of pyrido[2,1a]pyrrolo [3,4-c]isoquinoline hydrobromides having no additional radical-sensitive substituents. The developed protocol does not require column chromatography to purify target compounds and can be performed on a gram scale. The free bases can be obtained from the synthesized hydrobromides in quantitative yield by basification at rt. The use 2/4-(ortho-bromo/ iodophenyl)-substituted pyrrolylpyridinium bromides allows control over the chemoselectivity of the intramolecular arylation to give the monocyclization product starting from bromo/ iodo-substituents or biscyclization product starting from dibromo-derivatives to give the new 24π-electron hexacyclic phenalenoid doped with two nitrogens. The protocol is also applicable for the construction of the pyrido[2,1-a]pyrrolo [3,2c]isoquinoline backbone from N-unprotected pyrrolylpyridinium salts and, unlike the Pd-catalyzed version cyclization, avoids the deprotection step that is accompanied by isomerization.

Supporting Information
Supporting Information File 1 Experimental procedures, compound characterization data, X-ray diffraction experiment, and copies of NMR spectra of new compounds.