Simple synthesis of pyrrolo[3,2-e]indole-1-carbonitriles

Alkylation of 5-nitroindol-4-ylacetonitriles with ethyl chloroacetate, α-halomethyl ketones, and chloroacetonitrile followed by a treatment of the products with chlorotrimethylsilane in the presence of DBU gives 1-cyanopyrrolo[3,2-e]indoles substituted in position 2 with electron-withdrawing groups.

In our previous papers [13][14][15][16] we have shown that o-nitroarylacetonitriles alkylated and alkenylated at the α-position to the cyano group can be converted into indoles under basic conditions in the presence of a silylating agent.

Results and Discussion
Here we report a simple two-step procedure for the transformation of 5-nitroindol-4-ylacetonitriles into pyrrolo [3,2-e]indole-1-carbonitriles 6 bearing an additional electron-withdrawing Scheme 1: Synthesis of pyrrolo [3,2-e]indoles via VNS in 5-nitroindoles [6,12]. substituent at position 2. In our approach the starting material was 1-benzyloxymethyl-4-cyanomethyl-2-methyl-5-nitroindole (4) obtained via the VNS of hydrogen in 1-benzyloxymethyl-2methyl-5-nitroindole with 4-chlorophenoxyacetonitrile according to our earlier elaborated method [12]. Alkylation of the nitrile 4 with ethyl bromoacetate in the presence of K 2 CO 3 led to the expected cyanoester 5a in 68% yield, but the product contained some contaminants difficult to separate by crystallization or column chromatography. Searching for more convenient reaction conditions, we have found that this reaction proceeds satisfactorily in almost quantitative yield when diazabicycloundecene (DBU) was used as the base. Analogous alkylation with α-halomethyl ketones, chloroacetonitrile, chloroacetamide and cinnamyl bromide provided the expected alkylation products 5b-g in good yields (Scheme 2 and Table 1).
To find optimal conditions for cyclization of the model compound 5a we screened various combinations of base and a reagent promoting the cyclization. With chlorotrimethylsilane-triethylamine the reaction proceeded slowly, and the starting material was completely consumed after 24 h, but the product 6a was isolated in moderate 30% yield. However, when we replaced triethylamine with a stronger base, such as DBU, the reaction was completed in 30 min, and the product was isolated in 90% yield. Similarly, with N,Obis(trimethylsilyl)acetamide (BSA) the reaction was completed in 30 min giving 6a in 67% yield. With tributylchlorostannane combined with DBU the reaction proceeded slowly to form after 24 h product 6a in 72% yield. Methanesulfonyl and pivaloyl chlorides, in combination with DBU proved ineffective in this reaction giving a very low rate of conversion after 24 h. Thus, transformations of other nitriles 5b-g into pyrrolo[3,2- e]indoles 6 were performed in the DBU-chlorotrimethylsilane system, and the results are presented in Table 1. It is worth mentioning that the ketone 5d upon reduction with SnCl 2 cyclized to pyrrolo[3,2-f]quinoline-9-carbonitrile 7 [17].
The removal of the benzyloxymethyl group from 1-(benzyloxymethyl)pyrrolo [3,2-e]indoles by catalytic hydrogenation has been described by Macor [6]. The hydroxy group from the N-hydroxypyrrole fragment can be removed by a procedure elaborated by us [18] employing α-bromoacetophenone in the presence of triethylamine as exemplified for pyrroloindoles 6a and 6d that were transformed under these conditions into the corresponding derivatives 8a and 8d (Scheme 2). The crude 3-hydroxy-pyrrolo[3,2-e]indole 6d without isolation and purification was subjected to dehydroxylation giving compound 8d in 47% yield.
A plausible route to the formation of 3-hydroxy-1-cyanopyrrolo[3,2-e]indoles is exemplified by the synthesis of 1,2dicyano derivative 6e from the dinitrile 5e (Scheme 3). In the first step the o-nitrobenzylic carbanion is silylated with trimethylchlorosilane to form trimethylsilyl nitronate A. Then a consecutive deprotonation forms another carbanion B at the β-position to the ring. The attack of this carbanion on the trimethylsilylnitronate results in the substitution of trimethoxysiloxyl and formation of C in that the fivemembered ring finally isomerizes to the N-hydroxypyrrole fragment of 6e.
To remove the benzyloxymethyl group from the compound 8a we adopted the procedure proposed by Macor [6]. Heating 8a with ammonium formate and 10% palladium on carbon as a catalyst in isopropanol in a sealed tube (95 °C) led to a mixture of the expected product 9a and the product 10a in that the cyano group was reduced to a methyl substituent (Scheme 4). There is a literature precedence [19] for similar transformations of cyanoarenes into corresponding methyl derivatives upon transfer hydrogenation with ammonium formate in the presence of palladium on a carbon catalyst.

Conclusion
In conclusion, the approach presented herein can be useful for the synthesis of variously substituted pyrrolo[3,2-e]indoles. The method does not require reductive conditions for the formation of the pyrrole ring and, thus, can be applicable for derivatives bearing sensitive substituents.

Experimental
Melting points (mp) are uncorrected. 1 H and 13 C NMR spectra were recorded on a Bruker Avance 500 or Varian vnmr s500 (both 500 MHz for 1 H and 125 MHz for 13 C spectra) instruments at 298 K. Chemical shifts δ are expressed in parts per million referenced to TMS; coupling constants J in hertz. IR spectra were recorded in KBr on a Perkin Elmer PE Spectrum 2000 spectrometer. Electron impact mass spectra (EI, 70 eV) were obtained on AMD-604 and AutoSpec Premier spectrometer. Electrospray mass spectra (ESI) were obtained on 4000 Q-TRAP and SYNAPT G2-S HDMS. Silica gel (Merck 60, 230-400 mesh) was used for column chromatography (CC). All reagents and solvents were of reagent grade or purified according to standard methods before use. 1-Benzyloxymethyl-4-(cyanomethyl)-2-methyl-5-nitroindole (4) was obtained by VNS of hydrogen in 1-benzyloxymethyl-2-methyl-5-nitroindole with 4-chlorophenoxyacetonitrile following our previously elaborated method [12].