Synthesis of nitrogen-containing heterocycles

Heterocycles are ring systems that incorporate at least one atom different from carbon in their ring system. Especially nitrogen-containing heterocycles like quinoxalines, indoles and indazoles are compounds of high interest in different fields of application.

Quinoxalines, a group of heterocyclic compounds consisting of a benzene and a pyrazine ring, have found various uses in biology and material science. They play crucial roles in the development of novel drugs due to their antibacterial, antiviral and antifungal properties. Moreover, they are widely studied for the use in optoelectronical applications like organic LEDs or organic solar cells. Quinoxaline polymers and oligomers such as the trimers hexaazatriphenylene and hexaazatrinaphtalene show interesting self-assembling qualities and can be used for battery electrodes

Figure 1: Quinoxalines and quinoxaline-based trimers.

As quinoxalines rarely occur in nature, the chemical synthesis of new quinoxaline-derived compounds is needed even more in order to test these extraordinary compounds regarding their properties for different applications. The easy accessibility of the starting compounds, the high stability of many quinoxalines and the variety of possible functionalizations increases the attractivity of this compound class in research.

Figure 2: Possible functionalizations of quinoxalines.

Different reactions can be used to create new quinoxaline derivatives and to study their usability in medicinical and optoelectronical approaches. New quinoxaline-based oligomers are in development to create large conjugated π system in order to investigate the efficiency of such conjugated system. Therefore, novel ways to synthesize controlled quinoxaline oligomers are studied to build tuneable systems.

Figure 3. Quinoxaline-based oligomers.

Indoles and indazoles are heterocyclic compounds which form valuable building blocks and end goals in pharmaceutical development and are also well-known designer drugs. Amongst them, 3-acylindoles are core elements of many biologically active heterocyclic compounds, various bioactive natural products, drugs and agrochemicals. So far, only a limited number of interesting new derivatives has been synthesized, therefore only a small number of compounds could be tested in biological experiments.

A methodology for the photoinduced synthesis of 3-acylated indazoles and indoles in a flow-microreactor will be developed for the ProMiSe project. The currently known methods for photoinduced synthesis, which have so far only been described for batch-synthesis, will be transferred to a continuous flow methodology in microreactors in order to improve the efficiency of the protocol with regard to the reaction time and safety aspects. In parallel, it will be tested to which extent are the reactions compatible with different catalysts, the tolerance of the functional groups will be examined as well as the core structure modification options. The application of the selected photoinduced reactions to the flow-model in microreactors will be used to develop strategies for the synthesis of various indole and indazole derivatives in order to establish a method for a systematic access to target compounds. The photoinduced key synthetic steps in the formation of indazoles and indoles are to be coupled technically with other necessary reactions and processes in flow. The extension of the protocol should lead to a multi-stage continuous flow process from commercial starting materials to the target compounds (synthetic routes A (Scheme 1) and B (Scheme 2)). To achieve this goal, the missing reactions necessary to complete the multi-step reaction have to be transferred to flow processes and (micro)reactors have to be added to the system. In addition, solutions to important challenges related to the purification of compounds in flow must be found for both synthetic routes. This includes the integration of liquid/liquid extraction and evaporation/removal of unwanted solvents.

Scheme 1: Multi-step synthetic route to acylated indoles using published procedures for azide introduction, photoinduced indazole generation and photoredox-catalyzed acylation.1,2,3

Scheme 2: Multi-step synthetic route to acylated indoles according to published procedures by Nakamura et al.4 and Zhang et al.5 (Batch synthesis)

Literature

  1. Scriven, E.F.V. & Turnbull, K. Azides: Their Preparation and Synthetic Uses. Chem. Rev. 88, 297–368 (1988).
  2. Selvam, K., Krishnakumar, R., Velmurugan, R. & Swaminathan, M. A simple one-pot nano titania mediated green synthesis of 2-alkylbenzimidazoles and indazole from aromatic azides under UV and solar light. Cat. Commun. 11, 280–284 (209).
  3. Jia, W., Jian, Y., Huang, B., Yang, C. & Xia, W. Photoredox-catalyzed Decarboxylative C-H Acylation of Heteroarenes. Synlett 29, 1881–1886 (2018).
  4. Nakamura, I., Yamagishi, U., Song, D., Konta, S. & Yamatoto, Y. Gold- and indium- catalysed synthesis of 3- and 6-sulfonylindoles from ortho-alkynyl-N-sulfonylanilines. Angew. Chemie – Int- Ed. 46, 2284–2287 (2007).
  5. Zhang, P., Xiao, T., Xiong, S., Dong, X. & Zhou, L. Syntesis of 3-Acylindoles by Visible-Light Induced Intramolecular Oxidative Cyclisation of o-Alkynylated N,N-Dialkylamines. Org. Lett. 16, 3264–3267 (2014).