Synthesis of substituted indoles using continuous flow micro reactors

Continuous flow micro fluidic devices for organic synthesis ('micro reactors') are becoming established in a number of facets of modern applied chemistry. As part of a concurrent research project with a pharmaceutical company for generation of materials of pharmaceutical interest within continuous flow environments, we present here, for the first time a series of indoles that have been produced within micro reactor systems. We have developed three different approaches to the synthesis, which are compared with traditional batch synthesis as well as each other in terms of ease of optimization, chemical suitability and versatility, and implications as to throughput. Typical throughputs of approach I (simulated classical synthesis) were in the region of 2 mgh(-1) of indoles such as tetrahydrocarbazole and cyclopentaindole. The second approach (based on Elk's modification of Fischer indole synthesis) gave throughputs of 5.7-8.9 mgh(-1) and the final approach (using heterocatalytic flow reactors) gave the highest throughputs of 12.7-20.1 mgh(-1). All throughputs are per single channel reactor system (i.e., one single reactor set up), and the latter two approaches produce viable output quantities for the syntheses of radiolabelled materials (where typically minute amounts of high purity materials are required from a rapid and safe production environment). (C) 2010 Elsevier Ltd. All rights reserved.