Synthesis of a 7-(aminomethyl)indole and related bis-indole derivatives

A 7-(aminomethyl)indole is a useful precursor to form a new range of unsymmetrical and symmetrical 3-substituted amide-, imine-, and amine-linked 7,7 ′ -bis-indoles. The reduction of an imine linked bis-indole leads to formation of the corresponding amine-linked bis-indole.


Introduction
The aminomethyl moiety is found in many indole alkaloids which possess biological activity. 1 For example, brassinin 1 and cyclobrassinin 2, are representative members of the phytoalexin family that have been isolated from cabbage and exhibit antitumor activity. 2During the last two decades, approximately thirty phytoalexins have been isolated from cruciferous plants.The key intermediate for the synthesis of the phytoalexins is 3-aminomethylindole 3. 3 More complex indoles such as bis-indoles are also very important biologically active scaffolds as they are found in many pharmacologically active alkaloids. 4Moreover, aminomethylindole based bis-indoles have been isolated from natural sources and demonstrate potential as biologically active compounds and useful synthetic targets.For example, bis-indole 4 has been isolated from the roots of Antirhea lucida, and synthesized from tryptamine derivatives through acid catalysed nucleophilic substitution of 1-hydroxytryptamine. 5 Given the various potential applications of bis-indoles, it is important to develop new classes of natural and unnatural bis-indole derivatives.This development can be greatly facilitated by the use of activated indoles which are capable of undergoing reaction at the C7 position.

Results and Discussion
Reduction of the 7-cyanoindole 6 5 was carried out using lithium aluminium hydride in tetrahydrofuran and gave exclusively the 7-aminomethylindole 6 in 73% yield (Scheme 1).The infrared spectrum of the amine 6 showed the characteristic absorptions of the primary amino group at 3368 and 3360 cm -1 .The formation of the amine was also deduced from the alkyl protons being present in the 1 H NMR spectrum at 4.15 ppm and a CH 2 signal appearing in the DEPT135 experiment.An m/z of 316.0973 was also obtained via high resolution mass spectrometry that was consistent with the target structure 6.
For the construction of 7,7′-linked-bis-indoles two basic strategies have been used.The first involves the formation of symmetrical and unsymmetrical bis-indoles by joining the 7aminomethyindole scaffold to mono-and bi-functional acyl chloride linkers such as 7trichloroacetylindole, oxalyl chloride and adipoyl chloride.The amide functionality is one of the most prevalent structural moieties present in polymers, natural products and pharmaceuticals. 7ccordingly, the first target 7,7′-bis-indole carboxamide 8 was prepared in 83% yield by the reaction of equimolar amounts of 7-aminomethyindole 6 and 7-trichloroacetylindole 7 8 in hot acetonitrile (Scheme 2).The construction of amide linked bis-indoles 9 and 10 was achieved by the treatment of the indole 6 with 0.5 equivalents of oxalyl chloride and adipoyl chloride respectively in the presence of triethylamine in dichloromethane.Both of the reactions were complete in an hour and the bisindoles 9 and 10 were afforded in 81% and 86% yield respectively.In the 1 H NMR spectrum of compound 10, for example, the amide NH appeared as a triplet at 8.27 ppm, while the indole NH resonance was observed at 10.91 ppm.The high chemical shift is indicative of strong intramolecular hydrogen bonding.Compound 10 also showed good solubility in deuterated dimethyl sulfoxide, allowing observation of a carbonyl resonance at 173 ppm in the 13 C NMR spectrum.Moreover, the CH 2 group resonance was determined both with 13 C DEPT135 NMR experiments.
The second strategy was to combine two different indole units which have different functionality, under suitable reaction conditions to form unsymmetrical bis-indoles.
Consequently, the condensation of 7-aminomethylindole 6 with indole-7-carbaldehyde 9 11 in ethanol gave the imine bis-indole 12 in 75% yield (Scheme 2).The 1 H NMR spectrum showed the imine proton at 8.91 ppm and the indole NH resonances at 11.38 ppm and 11.49 ppm, indicating the presence of strong hydrogen bonding within the system.The protons of the four methoxy groups appeared at 3.82, 3.89, 3.90, 3.94 ppm and the H5 and H5′ protons at 6.46 ppm and 6.49 ppm confirming the unsymmetrical nature of the structure.A high resolution mass spectrum further confirmed the structure, showing a molecular ion at 614.1599 (M+Na) + .In general, secondary amines have also been prepared from the imines via catalytic hydrogenation and reduction with sodium and alcohol. 10ollowing this, the desired amine 13 was prepared by heating the imine 12 with sodium borohydride at reflux in a mixture of ethanol and tetrahydrofuran (Scheme 2).The 1 H NMR spectrum of the compound 13 indicated an indole amine, as expected, in combination with the disappearance of the imine bond resonance and the presence of CH 2 resonance at 4.01 ppm, which clearly indicated that the reaction occurred across the double bond as anticipated.Also, ESI mass spectral analysis showed a molecular ion at 616.1768 (M+H) + .

Conclusions
In summary, 7-aminomethylindole 6 was synthesised by reduction of the corresponding 7cyanoindole 5, and proved to be a useful precursor for a range of 7,7′-bis-indoles.The amide linked bis-indoles were obtained upon reaction of 7-aminomethylindole 6 with acyl chlorides, while an imine linked compound 12 was produced upon reaction with 7-formylindole 11.The corresponding amine linked bis-indole 13 was obtained through reduction of the imine linkage with sodium borohydride.It is noteworthy that the bis-indoles all contain a nucleophilic unsubstituted C2 position that provides scope for further functionalisation.This rather limited study provides the basis for a simple and general route to a wide range of potentially interesting bis-indole compounds.

Experimental Section
General.All reagents and solvents were obtained from commercial sources and appropriately purified, if necessary.Melting points were measured using a Mel-Temp melting point apparatus.Microanalyses were performed on a Carlo Erba Elemental Analyses EA 1108 at the Campbell Microanalytical Laboratory, University of Otago, New Zealand. 1 H and 13 C NMR spectra were obtained on Bruker DPX300 and Bruker DPX600 spectrometers.Mass spectra were recorded on either a Bruker FT-ICR MS (EI) or a Micromass ZQ2000 (ESI).Infrared spectra were recorded with a Thermo Nicolet 370 FTIR Spectrometer using KBr discs.Pressure column chromatography was carried out using Merck 230-400 mesh ASTM silica gel.Vacuum column chromatography was performed using Merck 60H silica gel.Gravity column chromatography was conducted using Merck 70-230 mesh ASTM silica gel, whilst preparative thin layer chromatography was carried out using Merck silica gel 7730 60GF 254 .

Figure 1 .
Figure 1.Examples of biologically active aminomethylindoles and derived compounds.