Synthesis of novel BIS-indole systems

Abstract

The primary aim of this project was to synthesize novel 2,2′- and 7,7′-linked bis-indole systems from methoxy activated indoles, and investigate their ability to undergo nucleophilic substitution reactions at C7 and C2 respectively. As an integral part of achieving this aim, the development of a new series of methoxy activated indole precursors was investigated. The construction of hydrazine bridged 2,2′- and 7,7′-linked bis-indoles was achieved from 2- and 7-glyoxylchlorides and 2- and 7- trichloroacetylindoles respectively. An efficient method was developed for the preparation of 7,7′-bis-indoles containing an oxadiazole derived spacer unit via the cyclodehydration of 7,7′- hydrazide linked bis-indoles. The preparation of a series of monomeric 1,3,4-thiadiazoles was also successfully achieved via the cyclodehydration of 2- and 7-thiosemicarbazides. Some of these 7,7′-hydrazine bridged bis-indoles showed promising antibacterial activity against both Gram positive and Gram negative bacteria. Based on these interesting biological results, some novel 7-carbohydrazides and 7-carboxamides were prepared in order to determine the effect of other substituents at the C7 position. A 7-aminomethylindole was synthesised by the reduction of the corresponding 7-cyanoindole and used as a functional precursor to prepare a range of 7,7′-bis-indoles Also, the reduction of 7-nitroethyl indoles led to the formation of 7-tryptamine analogues. These were used to generate amide and imine linked 7,7′-bis-indoles and for the construction of imine linked macrocycles, which were subsequently reduced to the corresponding amine linked macrocycles. 7-Bromoindoles are key intermediates for the synthesis of biindolyl systems. However, all attempts to synthesize 7-bromoindoles failed, but interestingly led to the generation of unexpected compounds such as 4,6-dimethoxybenzotriazole. This led to the subsequent investigation of the C7 reactivity of this system by exploring reactions such as formylation, acylation and acid catalysed dimerization. The synthesis of 7-oxotryptamines was accomplished via hydrogenation of the corresponding 7-acyl cyanides. 7-Oxotryptamines were subsequently reacted with 7-trichloroacetyindoles to form amide linked bis-indoles, which were converted to the oxazole linked bis-indoles. Some monomeric 7-methyloxazoles were also prepared from the 7-keto amides via cyclodehydration. However, the synthesis of 7-hydroxy tryptamine was unsuccessful and led to the formation of a dimer and an alcohol.