Synthesis of furano[2,3-g ]indoles from activated indoles

3-(4-Chlorophenyl)-6-hydroxy-4-methoxy-1-(toluene-4-sulfonyl)indole-7-carbaldehyde undergoes alkylation at the phenolic OH group with α -haloketones to give the corresponding ethers which can be cyclised with further base treatment to give N -tosylated furano[2,3-g ]indoles. The indole NH can then be deprotected using potassium hydroxide in methanol to give furano[2,3-g ]indoles.

We have recently reported 13 the preparation of the 6-hydroxy-4-methoxyindole-7-carbaldehyde 7, and consequently the possible synthesis of examples of the novel tricyclic systems 1 and 2 was investigated (Scheme 1).While reaction at C5 is not usually observed in 4,6-dimethoxyindoles, it can occur in the less well protected 4-methoxy-6-hydroxyindoles.Several aspects of the following work have been mentioned in the report of a conference lecture. 14

Possible reaction paths
The benzofuran ring system, which is a substructure of the tricyclic structures 1 and 2, can be synthesized from salicylaldehydes or activated phenols via α-aryloxyketones in two steps. 15,16The successful application of those reactions to the 6-hydroxyindole 7 would possibly give derivatives of the heterocyclic scaffolds 1 and 2 (Scheme 1).

Base catalyzed alkylation and cyclisation
In order to avoid alkylation of the indole NH, the N-tosyl-protected 6-hydroxyindole 7 was chosen over a related unprotected indole.Alkylation of indole 7 with α-haloketones or esters would provide indolo-ethers, which could then potentially undergo intramolecular cyclisation to give derivatives of either the furano[2,3g]indole 2 or the furano[3,2-f]indole 1.
Preliminary experiments showed that the best results were obtained with potassium carbonate in boiling acetone.Other reaction conditions, such as sodium bicarbonate in acetone, potassium carbonate in ethanol, or sodium hydride in tetrahydrofuran, gave rather poor conversions or yielded product mixtures.Consequently, reaction of indole 7 with ethyl bromoacetate gave the indole ether 8 in 68% yield.A similar reaction with 2-bromopropiophenone gave the indole ether 9 in 62% yield.On the other hand, reaction of indole 7 with 2-bromoacetophenone and 2-bromo-4'-chloroacetophenone gave the furanoindoles 13 and 14 respectively, presumably via unstable indole ethers 10 and 11 respectively.The ether 10 could be isolated using a shorter reaction time, but was unstable and underwent rapid cyclisation to the furanoindole 13: the ether 11 could not be isolated.Reaction of indole 7 with chloroacetone simply gave the furanoindole 15, without any isolation or detection of the presumed intermediate 12 (Scheme 2).
Attempts to extend this cyclisation process to the indole ester 8 failed.The use of stronger bases, such as sodium ethoxide or sodium hydroxide, did not afford the cyclised product, but instead yielded the related free carboxylic acid 17 after work-up.Furthermore, base-catalysed cyclisation attempts with indole ether 9 resulted only in recovered starting material, since the intermediate cyclisation product is not able to aromatise to the furan ring.
The tosyl group of the furanoindoles 13-15 could be removed easily with crushed potassium hydroxide in refluxing methanol, yielding the furanoindoles 18-20 respectively in 73-91% yield.The structures of these furanoindoles were confirmed by 1D and 2D NMR experiments.

Acid-catatysed cyclisation
On the basis that the synthesis of benzofurans can be achieved by intramolecular cyclisation from αaryl(alkyl)oxyketones in the presence of trifluoroacetic acid, 8,9 cyclisation of indole ethers 9 and 10 was attempted to give furano[3,2-f]indoles of type 1.However, formation of the desired furano[3,2-f]indoles was not observed: indole ether 10 gave the furano[2,3-g]indole 13, but indole ether 9 failed to react and only starting material was recovered.

Reduction of the carbonyl group
The carbonyl groups on the furanoindoles 18 and 20 were easily reduced using sodium borohydride in ethanol, giving excellent yields of the corresponding stable alcohols 22 and 23 (Scheme 2).These alcohols were of interest in that they incorporate a nucleophilic site at the indole C2 and an electrophilic site at the hydroxymethyl group of the furan ring.However, treatment of the alcohols 22 and 23 under a variety of acidic conditions led only to complex polymeric mixtures.

Experimental Section
General.Melting points were measured using a Mel-Temp melting point apparatus.Microanalyses were performed on Carlo Erba Elemental Analyser EA 1108 at the Campbell Microanalytical Laboratory, University of Otago, New Zealand.
1H and13C NMR spectra were obtained on a Bruker DPX300 (300 MHz) spectrometer and internally referenced to solvent peaks.Mass spectra were recorded on either a Bruker Daltonics Bio Apex II FTICR MS (HRMS-ESI) at the School of Chemistry, University of New South Wales, or a Shimadzu LCMS QP 8000 (EI) at the Univeristy of Otago, New Zealand.Infrared spectra were recorded with a Thermo Nicolet 370 FTIR Spectrometer using KBr discs.Ultraviolet-visible spectra were recorded using a Varian Cary 100 Scan Spectrometer.