Abstract
A one-pot, three-component protocol for the synthesis of 1,2,3-trisubstituted indoles has been developed, based upon a Fischer indolisation-indole N-alkylation sequence. This procedure is very rapid (total reaction time under 30 minutes), operationally straightforward, generally high yielding and draws upon readily available building blocks (aryl hydrazines, ketones, alkyl halides) to generate densely substituted indole products. We have demonstrated the utility of this process in the synthesis of 23 indoles, benzoindoles and tetrahydrocarbazoles bearing varied and useful functionality.
Highlights
Indole synthesis has a long and distinguished history, and the many published protocols for generating and elaborating the indole core ensure that few indole structures are beyond the reach of the present-day synthetic chemist.[13,14,15,16,17]
Our recent studies into structurally-diverse spiropyrans[4,18] required a broad range of 1,2,3-trisubstituted indole building blocks and, to meet this demand, we have developed a rapid, cheap and concise one-pot, three-component sequence for their synthesis, based upon Fischer indolisation–N-alkylation, and the evolution of this process is described
Analytical thin layer chromatography was carried out using Merck Kieselgel 60 F254, coated on aluminium plates, with visualisation of spots where necessary by quenching of UV (254 nm) fluorescence
Summary
Indoles are prominent in natural and non-natural products of biological and pharmaceutical importance, and are often considered as a “privileged scaffold” within the drug discovery arena.[1,2] they are versatile building blocks in synthesis, providing access to diverse heterocycles (e.g. tryptolines,[3] spiropyrans,[4] indolines,[5] oxindoles[6] and spirocycles7), substrates for asymmetric dearomatisation,[8,9] and polymers and composite materials with energy storage and biomedical applications.[10,11,12] indole synthesis has a long and distinguished history, and the many published protocols for generating and elaborating the indole core ensure that few indole structures are beyond the reach of the present-day synthetic chemist.[13,14,15,16,17] Our recent studies into structurally-diverse spiropyrans[4,18] required a broad range of 1,2,3-trisubstituted indole building blocks and, to meet this demand, we have developed a rapid, cheap and concise one-pot, three-component sequence for their synthesis, based upon Fischer indolisation–N-alkylation, and the evolution of this process is described .[19]. With respect to competing C-3 alkylation, our suspicion was that incomplete deprotonation was allowing direct reaction of 2,3-dimethylindole with benzyl bromide (via C-3), and this was due to poor solubility of hydride and the indole anion in solvent mixtures containing THF This hypothesis was supported by the observation that alkylation in media containing an increased proportion of DMF displayed a slight but significant shift towards reaction through nitrogen (compare entries 3 and 7). Whilst reactions at 50 °C and 65 °C offered modest improvements in regioselectivity, we were delighted to observe complete N-alkylation at 80 °C, and this corresponded to 91% isolated yield (96% per step) of the desired 1,2,3-trisubstituted indole 4a Further development of this process identified that the DMF volume could be halved without detriment at this elevated temperature (entry 11) (further reduction resulted in reduced regioselectivity) and that alkylation was complete in under 15 minutes (entries 12 and 13). This can be attributed to the volatility of this reagent at 80 °C, despite the reaction occurring in a sealed tube (Table 3)
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